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Hirai T, Umeda N, Harada T, Okumura A, Nakayasu C, Ohto‐Nakanishi T, Tsuchiya KJ, Nishimura T, Matsuzaki H. Arachidonic acid-derived dihydroxy fatty acids in neonatal cord blood relate symptoms of autism spectrum disorders and social adaptive functioning: Hamamatsu Birth Cohort for Mothers and Children (HBC Study). Psychiatry Clin Neurosci 2024; 78:546-557. [PMID: 39041066 PMCID: PMC11488600 DOI: 10.1111/pcn.13710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 05/21/2024] [Accepted: 06/16/2024] [Indexed: 07/24/2024]
Abstract
AIM Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega-6 to omega-3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children. METHODS This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS-2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS-II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers. RESULTS Arachidonic acid-derived diols, 11,12-diHETrE was found to impact ASD symptom severity on the ADOS-2-calibrated severity scores and impairment in the socialization domain as assessed by the VABS-II (P = 0.0003; P = 0.004, respectively). High levels of 11,12-diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9-diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls. CONCLUSION These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology.
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Affiliation(s)
- Takaharu Hirai
- Department of Psychiatric and Mental Health Nursing, School of NursingUniversity of FukuiEiheijiJapan
- Life Science Innovation CenterUniversity of FukuiEiheijiJapan
| | - Naoko Umeda
- Life Science Innovation CenterUniversity of FukuiEiheijiJapan
- Department of Maternal and Child Health Nursing, School of NursingUniversity of FukuiEiheijiJapan
| | - Taeko Harada
- Research Center for Child Mental DevelopmentHamamatsu University School of MedicineHamamatsuJapan
- United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of MedicineChiba University and University of FukuiSuitaJapan
| | - Akemi Okumura
- Research Center for Child Mental DevelopmentHamamatsu University School of MedicineHamamatsuJapan
- United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of MedicineChiba University and University of FukuiSuitaJapan
| | - Chikako Nakayasu
- Research Center for Child Mental DevelopmentHamamatsu University School of MedicineHamamatsuJapan
| | | | - Kenji J. Tsuchiya
- Research Center for Child Mental DevelopmentHamamatsu University School of MedicineHamamatsuJapan
- United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of MedicineChiba University and University of FukuiSuitaJapan
| | - Tomoko Nishimura
- Research Center for Child Mental DevelopmentHamamatsu University School of MedicineHamamatsuJapan
- United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of MedicineChiba University and University of FukuiSuitaJapan
| | - Hideo Matsuzaki
- United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of MedicineChiba University and University of FukuiSuitaJapan
- Research Center for Child Mental DevelopmentUniversity of FukuiEiheijiJapan
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Slišković AM, Palić J, Božina T, Ganoci L, Vrkić Kirhmajer M, Trkulja V, Bulum J, Šimičević L. Common P-glycoprotein ( ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events: Preliminary data. Biochem Med (Zagreb) 2024; 34:020703. [PMID: 38665866 PMCID: PMC11042566 DOI: 10.11613/bm.2024.020703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/16/2024] [Indexed: 04/28/2024] Open
Abstract
Introduction Considering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. Materials and methods We report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the "load" of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. Results There were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. Conclusions The evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.
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Affiliation(s)
- Ana Marija Slišković
- Department of Cardiovascular Diseases, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Jozefina Palić
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Tamara Božina
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Lana Ganoci
- Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Majda Vrkić Kirhmajer
- Department of Cardiovascular Diseases, University Hospital Centre Zagreb, Zagreb, Croatia
- Department of Internal Medicine, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Vladimir Trkulja
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Joško Bulum
- Department of Cardiovascular Diseases, University Hospital Centre Zagreb, Zagreb, Croatia
- Department of Internal Medicine, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Livija Šimičević
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, University of Zagreb School of Medicine, Zagreb, Croatia
- Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
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Leow JWH, Chan ECY. CYP2J2-mediated metabolism of arachidonic acid in heart: A review of its kinetics, inhibition and role in heart rhythm control. Pharmacol Ther 2024; 258:108637. [PMID: 38521247 DOI: 10.1016/j.pharmthera.2024.108637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 02/06/2024] [Accepted: 03/11/2024] [Indexed: 03/25/2024]
Abstract
Cytochrome P450 2 J2 (CYP2J2) is primarily expressed extrahepatically and is the predominant epoxygenase in human cardiac tissues. This highlights its key role in the metabolism of endogenous substrates. Significant scientific interest lies in cardiac CYP2J2 metabolism of arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, to regioisomeric bioactive epoxyeicosatrienoic acid (EET) metabolites that show cardioprotective effects including regulation of cardiac electrophysiology. From an in vitro perspective, the accurate characterization of the kinetics of CYP2J2 metabolism of AA including its inhibition and inactivation by drugs could be useful in facilitating in vitro-in vivo extrapolations to predict drug-AA interactions in drug discovery and development. In this review, background information on the structure, regulation and expression of CYP2J2 in human heart is presented alongside AA and EETs as its endogenous substrate and metabolites. The in vitro and in vivo implications of the kinetics of this endogenous metabolic pathway as well as its perturbation via inhibition and inactivation by drugs are elaborated. Additionally, the role of CYP2J2-mediated metabolism of AA to EETs in cardiac electrophysiology will be expounded.
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Affiliation(s)
- Jacqueline Wen Hui Leow
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
| | - Eric Chun Yong Chan
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
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Zou LL, Zhao FL, Qi YY, Wang SH, Zhou Q, Geng PW, Zhou YF, Zhang Q, Chen H, Dai DP, Cai JP, Ji FS. Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro. Front Pharmacol 2023; 14:1186824. [PMID: 37288113 PMCID: PMC10242136 DOI: 10.3389/fphar.2023.1186824] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/09/2023] [Indexed: 06/09/2023] Open
Abstract
Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.
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Affiliation(s)
- Li-Li Zou
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Fang-Ling Zhao
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Ying Qi
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuang-Hu Wang
- The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, China
| | - Quan Zhou
- The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, China
| | - Pei-Wu Geng
- The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, China
| | - Yun-Fang Zhou
- The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, China
| | - Qing Zhang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Hao Chen
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Da-Peng Dai
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Fu-Sui Ji
- The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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Abstract
Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction. Increased renin release by bioactive lipids in the kidney is pro-hypertensive whereas anti-hypertensive bioactive lipid actions result in increased sodium excretion. Bioactive lipids have pro-inflammatory and anti-inflammatory actions that increase or decrease reactive oxygen species and impact vascular and kidney function in hypertension. Human studies provide evidence that fatty acid metabolism and bioactive lipids contribute to sodium and blood pressure regulation in hypertension. Genetic changes identified in humans that impact arachidonic acid metabolism have been associated with hypertension. Arachidonic acid cyclooxygenase, lipoxygenase and cytochrome P450 metabolites have pro-hypertensive and anti-hypertensive actions. Omega-3 fish oil fatty acids eicosapentaenoic acid and docosahexaenoic acid are known to be anti-hypertensive and cardiovascular protective. Lastly, emerging fatty acid research areas include blood pressure regulation by isolevuglandins, nitrated fatty acids, and short chain fatty acids. Taken together, bioactive lipids are key contributors to blood pressure regulation and hypertension and their manipulation could decrease cardiovascular disease and associated morbidity and mortality.
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Affiliation(s)
- John D Imig
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
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Ongun MC, Tonyali NV, Kaplan O, Deger I, Celebier M, Basci Akduman NE, Sahin D, Yucel A, Babaoglu MO. Effects of genetic polymorphisms of CYP2J2, CYP2C9, CYP2C19, CYP4F2, CYP4F3 and CYP4A11 enzymes in preeclampsia and gestational hypertension. Placenta 2023; 137:88-95. [PMID: 37141740 DOI: 10.1016/j.placenta.2023.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 04/04/2023] [Accepted: 04/26/2023] [Indexed: 05/06/2023]
Abstract
INTRODUCTION The aim of this study was to investigate the effects of cytochrome P450 (CYP) 2J2, CYP2C9, CYP2C19 and CYP4F2, CYP4F3 and CYP4A11 genetic polymorphisms in preeclampsia and gestational hypertension (GHT) patients in a sample of Turkish population. MATERIALS-METHODS Patients (n = 168; 110 GHT and 58 preeclampsia) and healthy pregnant women (n = 155, controls) participated in the study. For genotyping, polymerase chain reaction (PCR) and restriction analysis (RFLP) were used. Substance levels were measured using LC-MS. RESULTS Plasma DHET levels in GHT and preeclampsia patients were significantly lower than those in the control group (62.7%, 66.3% vs.100.0%, respectively, p < 0.0001). An increase in CYP2J2*7 allele frequency was observed in the preeclampsia group, as compared to GHT group (12.1% vs. 4.5%; odds ratio, O.R. = 2.88, p < 0.01). The frequencies of CYP2C19*2 and*17 alleles were higher in GHT group as compared to the control group (17.7% vs. 11.6%, O.R. = 1.99, p < 0.01; and 28.6% vs.18.4%, O.R. = 2.03, p < 0.01, respectively). An increased frequency of CYP4F3 rs3794987 G allele was found in GHT group as compared to the control group (48.0% vs. 38.0%; O.R. = 1.53, p < 0.01). DISCUSSION DHET plasma levels were significantly reduced in hypertensive pregnant groups as compared to the control group. The allele frequency distributions for CYP2J2*7, CYP2C19 *2, *17 and CYP4F3 rs3794987 were significantly different in hypertensive pregnant patients as compared to the healthy control subjects. Our results may suggest that investigated genetic polymorphisms may be useful in diagnosis and clinical management of GHT and preeclampsia patients.
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Affiliation(s)
- Mert C Ongun
- Hacettepe University, Faculty of Medicine, Department of Medical Pharmacology, Ankara, Turkey.
| | | | - Ozan Kaplan
- Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
| | - Ilter Deger
- Hacettepe University, Faculty of Medicine, Department of Medical Pharmacology, Ankara, Turkey
| | - Mustafa Celebier
- Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
| | | | - Dilek Sahin
- University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Aykan Yucel
- University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Melih O Babaoglu
- Hacettepe University, Faculty of Medicine, Department of Medical Pharmacology, Ankara, Turkey
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Li Y, You C, Liu Z, He F, Zhao F, Song X, Xie Z, Wei S, Yang Y, Wei H, Che F, Yu J. CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2023; 32:106974. [PMID: 36587509 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/11/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Many studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. METHODS Forty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. RESULTS We found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. CONCLUSIONS CYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.
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Affiliation(s)
- Yue Li
- Qingdao University, Qingdao, Shandong, China; Department of Neurology, Linyi People's Hospital, Linyi, Shandong, China
| | - Cuiping You
- Central Laboratory, Linyi People's Hospital, Linyi, Shandong, China
| | - Zhenchuan Liu
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Feng He
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Fuchun Zhao
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Xiaojie Song
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Zhongxiang Xie
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Shuai Wei
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Yongfang Yang
- Rehabilitation department, Linyi People's Hospital, Linyi, Shandong, China
| | - Hongyan Wei
- Department of Neurological Intensive Care Unit, Linyi People's Hospital, Linyi, Shandong, China
| | - Fengyuan Che
- Central Laboratory, Linyi People's Hospital, Linyi, Shandong, China.
| | - Jixu Yu
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong, China.
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Nayeem MA, Geldenhuys WJ, Hanif A. Role of cytochrome P450-epoxygenase and soluble epoxide hydrolase in the regulation of vascular response. ADVANCES IN PHARMACOLOGY 2023; 97:37-131. [DOI: 10.1016/bs.apha.2022.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Nayeem MA, Hanif A, Geldenhuys WJ, Agba S. Crosstalk between adenosine receptors and CYP450-derived oxylipins in the modulation of cardiovascular, including coronary reactive hyperemic response. Pharmacol Ther 2022; 240:108213. [PMID: 35597366 DOI: 10.1016/j.pharmthera.2022.108213] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 12/14/2022]
Abstract
Adenosine is a ubiquitous endogenous nucleoside or autacoid that affects the cardiovascular system through the activation of four G-protein coupled receptors: adenosine A1 receptor (A1AR), adenosine A2A receptor (A2AAR), adenosine A2B receptor (A2BAR), and adenosine A3 receptor (A3AR). With the rapid generation of this nucleoside from cellular metabolism and the widespread distribution of its four G-protein coupled receptors in almost all organs and tissues of the body, this autacoid induces multiple physiological as well as pathological effects, not only regulating the cardiovascular system but also the central nervous system, peripheral vascular system, and immune system. Mounting evidence shows the role of CYP450-enzymes in cardiovascular physiology and pathology, and the genetic polymorphisms in CYP450s can increase susceptibility to cardiovascular diseases (CVDs). One of the most important physiological roles of CYP450-epoxygenases (CYP450-2C & CYP2J2) is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) which generally involve in vasodilation. Like an increase in coronary reactive hyperemia (CRH), an increase in anti-inflammation, and cardioprotective effects. Moreover, the genetic polymorphisms in CYP450-epoxygenases will change the beneficial cardiovascular effects of metabolites or oxylipins into detrimental effects. The soluble epoxide hydrolase (sEH) is another crucial enzyme ubiquitously expressed in all living organisms and almost all organs and tissues. However, in contrast to CYP450-epoxygenases, sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and others and reverses the beneficial effects of epoxy-fatty acids leading to vasoconstriction, reducing CRH, increase in pro-inflammation, increase in pro-thrombotic and become less cardioprotective. Therefore, polymorphisms in the sEH gene (Ephx2) cause the enzyme to become overactive, making it more vulnerable to CVDs, including hypertension. Besides the sEH, ω-hydroxylases (CYP450-4A11 & CYP450-4F2) derived metabolites from AA, ω terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD2, PGF2α; thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, reduction in CRH, pro-inflammation and cardiac toxicity. Interestingly, the interactions of adenosine receptors (A2AAR, A1AR) with CYP450-epoxygenases, ω-hydroxylases, sEH, and their derived metabolites or oxygenated polyunsaturated fatty acids (PUFAs or oxylipins) is shown in the regulation of the cardiovascular functions. In addition, much evidence demonstrates polymorphisms in CYP450-epoxygenases, ω-hydroxylases, and sEH genes (Ephx2) and adenosine receptor genes (ADORA1 & ADORA2) in the human population with the susceptibility to CVDs, including hypertension. CVDs are the number one cause of death globally, coronary artery disease (CAD) was the leading cause of death in the US in 2019, and hypertension is one of the most potent causes of CVDs. This review summarizes the articles related to the crosstalk between adenosine receptors and CYP450-derived oxylipins in vascular, including the CRH response in regular salt-diet fed and high salt-diet fed mice with the correlation of heart perfusate/plasma oxylipins. By using A2AAR-/-, A1AR-/-, eNOS-/-, sEH-/- or Ephx2-/-, vascular sEH-overexpressed (Tie2-sEH Tr), vascular CYP2J2-overexpressed (Tie2-CYP2J2 Tr), and wild-type (WT) mice. This review article also summarizes the role of pro-and anti-inflammatory oxylipins in cardiovascular function/dysfunction in mice and humans. Therefore, more studies are needed better to understand the crosstalk between the adenosine receptors and eicosanoids to develop diagnostic and therapeutic tools by using plasma oxylipins profiles in CVDs, including hypertensive cases in the future.
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Affiliation(s)
- Mohammed A Nayeem
- Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA.
| | - Ahmad Hanif
- Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - Werner J Geldenhuys
- Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - Stephanie Agba
- Graduate student, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA
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Zhang Y, Gao L, Yao B, Huang S, Zhang Y, Liu J, Liu Z, Wang X. Role of epoxyeicosatrienoic acids in cardiovascular diseases and cardiotoxicity of drugs. Life Sci 2022; 310:121122. [DOI: 10.1016/j.lfs.2022.121122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 11/09/2022]
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Abstract
INTRODUCTION Cytochrome P450s (CYPs) are a superfamily of monooxygenases with diverse biological roles. CYP2J2 is an isozyme highly expressed in the heart where it metabolizes endogenous substrates such as N-3/N-6 polyunsaturated fatty acids (PUFA) to produce lipid mediators involved in homeostasis and cardioprotective responses. Expanding our knowledge of the role CYP2J2 has within the heart is important for understanding its impact on cardiac health and disease. AREAS COVERED The objective of this review was to assess the state of knowledge regarding cardiac CYP2J2. A literature search was conducted using PubMed-MEDLINE (from 2022 and earlier) to evaluate relevant studies regarding CYP2J2 mediated cardioprotection, small molecule modulators, effects of CYP2J2 substrates toward biologically relevant effects and implications of CYP2J2 polymorphisms and sexual dimorphism in the heart. EXPERT OPINION Cardiac CYP2J2-mediated metabolism of endogenous and exogenous substrates have been shown to impact cardiac function. Identifying individual factors, like sex and age, that affect CYP2J2 require further elucidation to better understand CYP2J2's clinical relevance. Resolving the biological targets and activities of CYP2J2-derived PUFA metabolites will be necessary to safely target CYP2J2 and design novel analogues. Targeting CYP2J2 for therapeutic aims offers a potential novel approach to regulating cardiac homeostasis, drug metabolism and cardioprotection.
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Sosnowski DK, Jamieson KL, Darwesh AM, Zhang H, Keshavarz-Bahaghighat H, Valencia R, Viveiros A, Edin ML, Zeldin DC, Oudit GY, Seubert JM. Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy. Front Cardiovasc Med 2022; 9:879209. [PMID: 35665247 PMCID: PMC9160304 DOI: 10.3389/fcvm.2022.879209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Metabolites derived from N−3 and N−6 polyunsaturated fatty acids (PUFAs) have both beneficial and detrimental effects on the heart. However, contribution of these lipid mediators to dilated cardiomyopathy (DCM)-associated mitochondrial dysfunction remains unknown. This study aimed to characterize DCM-specific alterations in the PUFA metabolome in conjunction with cardiac mitochondrial quality in human explanted heart tissues. Methods Left ventricular tissues obtained from non-failing control (NFC) or DCM explanted hearts, were assessed for N−3 and N−6 PUFA metabolite levels using LC-MS/MS. mRNA and protein expression of CYP2J2, CYP2C8 and epoxide hydrolase enzymes involved in N−3 and N−6 PUFA metabolism were quantified. Cardiac mitochondrial quality was assessed by transmission electron microscopy, measurement of respiratory chain complex activities and oxygen consumption (respiratory control ratio, RCR) during ADP-stimulated ATP production. Results Formation of cardioprotective CYP-derived lipid mediators, epoxy fatty acids (EpFAs), and their corresponding diols were enhanced in DCM hearts. These findings were corroborated by increased expression of CYP2J2 and CYP2C8 enzymes, as well as microsomal and soluble epoxide hydrolase enzymes, suggesting enhanced metabolic flux and EpFA substrate turnover. DCM hearts demonstrated marked damage to mitochondrial ultrastructure and attenuated mitochondrial function. Incubation of fresh DCM cardiac fibers with the protective EpFA, 19,20-EDP, significantly improved mitochondrial function. Conclusions The current study demonstrates that increased expressions of CYP-epoxygenase enzymes and epoxide hydrolases in the DCM heart correspond with enhanced PUFA-derived EpFA turnover. This is accompanied by severe mitochondrial functional impairment which can be rescued by the administration of exogenous EpFAs.
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Affiliation(s)
- Deanna K. Sosnowski
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - K. Lockhart Jamieson
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Ahmed M. Darwesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Hao Zhang
- Department of Medicine, Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
| | | | - Robert Valencia
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Anissa Viveiros
- Department of Medicine, Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
| | - Matthew L. Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Durham, NC, United States
| | - Darryl C. Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Durham, NC, United States
| | - Gavin Y. Oudit
- Department of Medicine, Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
| | - John M. Seubert
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB, Canada
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: John M. Seubert
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Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts. Acta Pharm Sin B 2022; 12:3905-3923. [PMID: 36213535 PMCID: PMC9532722 DOI: 10.1016/j.apsb.2022.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 01/08/2023] Open
Abstract
Cytochrome P4502J2 (CYP2J2) metabolizes arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs). Dronedarone, an antiarrhythmic drug prescribed for treatment of atrial fibrillation (AF) induces cardiac adverse effects (AEs) with poorly understood mechanisms. We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly, disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment. In this study, we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs. We first synthesized a deuterated analogue of dronedarone (termed poyendarone) and demonstrated that it neither inactivates CYP2J2, disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro. Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration. Next, we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat (BTB) variability reflective of proarrhythmic phenotype. In contrast, poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity. Importantly, poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF, while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk. Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.
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Imig JD. Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury. ADVANCES IN PHARMACOLOGY 2022; 94:27-55. [PMID: 35659375 PMCID: PMC10105514 DOI: 10.1016/bs.apha.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression. Furthermore, evidence in human and experimental animal studies have found that decreased EET levels contribute to hypertension and kidney diseases. Consequently, EET mimics/analogs have been developed as a potential therapeutic for hypertension and acute and chronic kidney diseases. Their development has resulted in EET analogs that are orally active with favorable pharmacological profiles. Analogs for 8,9-EET, 11,12-EET, and 14,15-EET have been tested in several hypertension and kidney disease animal models. More recently, kidney targeted EET analogs have been synthesized and tested against drug-induced nephrotoxicity. Experimental evidence has demonstrated compelling therapeutic potential for EET analogs to oppose cardiovascular and kidney diseases. These EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis. Overall, these preclinical studies support the likelihood that EET analogs will advance to clinical trials for hypertension and associated comorbidities or acute and chronic kidney diseases.
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Affiliation(s)
- John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States.
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15
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Gerges SH, El-Kadi AOS. Sex differences in eicosanoid formation and metabolism: A possible mediator of sex discrepancies in cardiovascular diseases. Pharmacol Ther 2021; 234:108046. [PMID: 34808133 DOI: 10.1016/j.pharmthera.2021.108046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/07/2021] [Accepted: 11/16/2021] [Indexed: 12/14/2022]
Abstract
Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes to produce prostaglandins, leukotrienes, epoxyeicosatrienoic acids (EETs), and hydroxyeicosatetraenoic acids (HETEs), along with other eicosanoids. Eicosanoids have important physiological and pathological roles in the body, including the cardiovascular system. Evidence from several experimental and clinical studies indicates differences in eicosanoid levels, as well as in the activity or expression levels of their synthesizing and metabolizing enzymes between males and females. In addition, there is a clear state of gender specificity in cardiovascular diseases (CVD), which tend to be more common in men compared to women, and their risk increases significantly in postmenopausal women compared to younger women. This could be largely attributed to sex hormones, as androgens exert detrimental effects on the heart and blood vessels, whereas estrogen exhibits cardioprotective effects. Many of androgen and estrogen effects on the cardiovascular system are mediated by eicosanoids. For example, androgens increase the levels of cardiotoxic eicosanoids like 20-HETE, while estrogens increase the levels of cardioprotective EETs. Thus, sex differences in eicosanoid levels in the cardiovascular system could be an important underlying mechanism for the different effects of sex hormones and the differences in CVD between males and females. Understanding the role of eicosanoids in these differences can help improve the management of CVD.
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Affiliation(s)
- Samar H Gerges
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
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16
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Li H, Bradbury JA, Edin ML, Graves JP, Gruzdev A, Cheng J, Hoopes SL, DeGraff LM, Fessler MB, Garantziotis S, Schurman SH, Zeldin DC. sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae. J Clin Invest 2021; 131:129679. [PMID: 34591792 DOI: 10.1172/jci129679] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2-/-) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2-/- mice. Ephx2-/- mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2-/- macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2-/- macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.
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17
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Li H, He Y, Wang L, Xing S, Peng L, Yuan D, Jin T. Analysis of CYP2J2 mutations in the Chinese Uyghur population. Am J Transl Res 2021; 13:10871-10881. [PMID: 34650768 PMCID: PMC8507070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/07/2021] [Indexed: 06/13/2023]
Abstract
Genetic characteristics of CYP2J2 in different populations may be helpful to explore interethnic variability in drug response and disease susceptibility. There is no information about the genetic profile of CYP2J2 in the Chinese Uyghur population. We used PCR and first-generation sequencing technology to investigate CYP2J2 mutations in 100 unrelated healthy Chinese Uyghurs. The chi-square test was used to compare genotyping data of CYP2J2 in the Chinese Uyghur population with other ethnic groups. The SIFT and PolyPhen-2 online tools were used to predict the protein function of the novel nonsynonymous mutations in CYP2J2. CADD software was used to predict pathogenicity of the mutations. We found twenty-eight mutations in CYP2J2, five new mutations, three alleles (*1, *7 and *8), and three genotypes (*1/*1, *1/*7 and *1/*8) in the Chinese Uyghur population. The allele frequencies of CYP2J2 *1, *7 and *8 were 96%, 3.45%, and 0.5%, respectively. Interethnic comparison found that subgenotype *1 in Uyghur was significantly higher than in Taiwanese and African Americans, and *7 frequency in Uyghur was slightly lower than that in Taiwanese and African Americans (P<0.05); *8 was only found in Chinese Uyghur and Korean populations, with frequencies of 0.5% and 0.8%, respectively. Furthermore, the protein prediction results revealed that the five nonsynonymous mutations could influence protein structure and function. The observations of this study give rise to useful information on CYP2J2 mutations in Chinese Uyghurs, which may support future important clinical implications for the use of medications metabolized by CYP2J2.
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Affiliation(s)
- Haiyue Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest UniversityXi’an 710069, Shaanxi, China
| | - Yongjun He
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
| | - Li Wang
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
| | - Shishi Xing
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
| | - Linna Peng
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
| | - Dongya Yuan
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
| | - Tianbo Jin
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest UniversityXi’an 710069, Shaanxi, China
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu UniversityXianyang 712082, Shaanxi, China
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Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy. J Clin Med 2021; 10:jcm10173980. [PMID: 34501433 PMCID: PMC8432556 DOI: 10.3390/jcm10173980] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023] Open
Abstract
Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48-0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05-9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.
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Perrelli A, Retta SF. Polymorphisms in genes related to oxidative stress and inflammation: Emerging links with the pathogenesis and severity of Cerebral Cavernous Malformation disease. Free Radic Biol Med 2021; 172:403-417. [PMID: 34175437 DOI: 10.1016/j.freeradbiomed.2021.06.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/03/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin affecting 0.5% of the population and characterized by abnormally enlarged and leaky capillaries that predispose to seizures, neurological deficits, and intracerebral hemorrhage (ICH). CCM occurs sporadically or is inherited as dominant condition with incomplete penetrance and highly variable expressivity. Three disease genes have been identified: KRIT1 (CCM1), CCM2 and CCM3. Previous results demonstrated that loss-of-function mutations of CCM genes cause pleiotropic effects, including defective autophagy, altered reactive oxygen species (ROS) homeostasis, and enhanced sensitivity to oxidative stress and inflammatory events, suggesting a novel unifying pathogenetic mechanism, and raising the possibility that CCM disease onset and severity are influenced by the presence of susceptibility and modifier genes. Consistently, genome-wide association studies (GWAS) in large and homogeneous cohorts of patients sharing the familial form of CCM disease and identical mutations in CCM genes have led to the discovery of distinct genetic modifiers of major disease severity phenotypes, such as development of numerous and large CCM lesions, and susceptibility to ICH. This review deals with the identification of genetic modifiers with a significant impact on inter-individual variability in CCM disease onset and severity, including highly polymorphic genes involved in oxidative stress, inflammatory and immune responses, such as cytochrome P450 monooxygenases (CYP), matrix metalloproteinases (MMP), and Toll-like receptors (TLR), pointing to their emerging prognostic value, and opening up new perspectives for risk stratification and personalized medicine strategies.
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Affiliation(s)
- Andrea Perrelli
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy; CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy.
| | - Saverio Francesco Retta
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy; CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy.
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Liang T, Liang A, Zhang X, Wang Q, Wu H, He J, Jin T. The association study between CYP20A1, CYP4F2, CYP2D6 gene polymorphisms and coronary heart disease risk in the Han population in southern China. Genes Genomics 2021; 44:1125-1135. [PMID: 34302632 DOI: 10.1007/s13258-021-01125-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 06/16/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Coronary heart disease (CHD) is a disease that seriously harms human health. Genetic factors seriously affect the CHD susceptibility. The CYP20A1, CYP4F2 and CYP2D6 are important drug metabolism enzymes in the human body. OBJECTIVE We aimed to explore the association between CYP20A1, CYP4F2, CYP2D6 single nucleotide polymorphisms (SNPs) and CHD risk in the Chinese Southern Han population. METHODS Based on the 'case-control' experimental design (505 cases and 508 controls), we conducted an association study between 5 candidate SNPs selected from CYP20A1 (rs2043449), CYP4F2 (rs2108622, rs3093106, rs309310), CYP2D6 (rs1065852) and CHD risk. Logistic regression was used to analyze the CHD susceptibility under different genetic models. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction of 'SNP-SNP' in CHD risk. RESULTS Our results showed that under multiple genetic models, CYP2D6 rs1065852 significantly increased the CHD risk in these participants who are ≤ 60 years old (OR 1.40, CI 1.07-1.82, p = 0.013), smokers (OR 1.40, CI 1.02-1.93, p = 0.039), or have family history (OR 1.24, CI 1.02-1.51, p = 0.035). CYP4F2 SNPs rs2108622 (OR 0.63, CI 0.43-0.93, p = 0.020), rs3093106 (OR 0.52, CI 0.29-0.92, p = 0.023), and rs309310 (OR 0.55, CI 0.31-0.96, p = 0.033) were potentially associated with the course of CHD patients. CONCLUSION Our study found that CY2D6 rs1065852 has an outstanding and significant association with increased CHD risk. Our study provided data supplements for CHD genetic susceptibility loci, and also provided a new and valuable reference for CHD drug treatment.
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Affiliation(s)
- Tiebiao Liang
- Department of Cardiovascular, People's Hospital of Wanning, The First Affiliated Hospital of Chongqing Medical University, Wanning, 571500, Hainan, China
| | - Anshan Liang
- Department of Cardiovascular, People's Hospital of Wanning, The First Affiliated Hospital of Chongqing Medical University, Wanning, 571500, Hainan, China
| | - Xianbo Zhang
- Department of Cardiovascular, People's Hospital of Wanning, The First Affiliated Hospital of Chongqing Medical University, Wanning, 571500, Hainan, China
| | - Qi Wang
- Department of General Practice, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, 570208, Hainan, China
| | - Haiqing Wu
- Department of Cardiovascular, People's Hospital of Wanning, The First Affiliated Hospital of Chongqing Medical University, Wanning, 571500, Hainan, China
| | - Jun He
- Department of Cardiovascular, People's Hospital of Wanning, The First Affiliated Hospital of Chongqing Medical University, Wanning, 571500, Hainan, China
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, 712082, Shaanxi, China.
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China.
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Acunha T, Nardini V, Peti APF, Prado MKB, Moraes LAB, Faccioli LH. Targeted analysis of eicosanoids derived from cytochrome P450 pathway by high-resolution multiple-reaction monitoring mass spectrometry. JOURNAL OF MASS SPECTROMETRY : JMS 2021; 56:e4769. [PMID: 34120382 DOI: 10.1002/jms.4769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 05/05/2021] [Accepted: 05/14/2021] [Indexed: 06/12/2023]
Abstract
Cytochrome P450 (CYP450) pathway is one of the critical enzymatic via eicosanoid biosynthesis. Nevertheless, their metabolites are far less explored. This pathway plays a crucial role in converting arachidonic acid to hydroxyeicosatetraenoic (HETEs), epoxyeicosatrienoic (EETs), dihydroxyeicosatetraenoic acids (DiHETEs), and dihydroxyeicosatrienoic acids (DiHETrEs), which mediate several physiological and pathological functions. However, CYP450-derived eicosanoids are structurally complex, making those analyses a challenge in lipidomics studies. Herein, a high-resolution multiple-reaction monitoring (MRMHR ) method has been proposed as a powerful tool for the simultaneous analysis of CYP450-eicosanoids on different biological samples. The developed liquid chromatography (LC)-MRMHR method was partially validated according to the Food and Drug Administration (FDA) criteria, demonstrating adequate specificity, linearity, precision, and accuracy. Besides, several biological samples were analyzed to guarantee the feasibility of the method. The proposed strategy may improve the understanding of CYP450-derived eicosanoids in biological systems, which could be fundamental to reveal new aspects of those in physiologic and pathologic conditions.
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Affiliation(s)
- Tanize Acunha
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Viviani Nardini
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Ana Paula Ferranti Peti
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Morgana Kelly Borges Prado
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Luiz Alberto Beraldo Moraes
- Department of Chemistry, School of Philosophy Sciences and Letters of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Lúcia Helena Faccioli
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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22
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Zuo D, Pi Q, Shi Y, Luo S, Xia Y. Dihydroxyeicosatrienoic Acid, a Metabolite of Epoxyeicosatrienoic Acids Upregulates Endothelial Nitric Oxide Synthase Expression Through Transcription: Mechanism of Vascular Endothelial Function Protection. Cell Biochem Biophys 2021; 79:289-299. [PMID: 33811614 DOI: 10.1007/s12013-021-00978-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2021] [Indexed: 02/07/2023]
Abstract
The present study aimed to investigate the impacts and underlying mechanisms of 14,15-DHETs on eNOS and vascular endothelial functions. Bovine aortic endothelial cells (BAECs) were treated with various concentrations of 14, 15-DHET. The expressions of eNOS protein and mRNA were observed at different time points. The eNOS expression and phosphorylation were subsequently detected administered with 8,9-DHET, 11,12-DHET, and 14,15-DHET, respectively. Meanwhile, 14,15-DHET action on tube formation was observed in human umbilical vein endothelial cells (HUVECs). Finally, the aorta of male C57BL/6 mice was injected with 14,15-DHET via the tail vein. The impacts of 14,15-DHET (0.4 mg/kg body weight) on the expressions of eNOS protein and mRNA and endothelium-dependent vasodilation (EDV) were detected following 24 h. The expression of eNOS was greatly improved with the 14,15-DHET treatment compared with the BAECs, and eNOS phosphorylation sites at Ser1179, Ser635, and Thr497 were elevated. However, no statistically significant difference was revealed on total eNOS among the 8,9-DHET, 11,12-DHET, and 14,15-DHET treatment groups. Based on the upregulation of eNOS protein, eNOS mRNA levels were increased in BAECs and thoracic aorta of the male C57BL/6 mice treated with 14,15-DHET, suggesting that transcriptional activation was achieved in vascular eNOS. Moreover, 14,15-DHET enhanced tube formation abilities in HUVECs and acetylcholine(ACh)-induced EDV. These findings indicated that 14,15-DHET could improve the vascular endothelial diastolic functions of male C57BL/6 mice, and enhance the ability of tube formation, which might be related to the increase of eNOS expression.
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Affiliation(s)
- Deyu Zuo
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Qiangzhong Pi
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yunmin Shi
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Suxin Luo
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Xia
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Mota-Zamorano S, Robles NR, Lopez-Gomez J, Cancho B, González LM, Garcia-Pino G, Navarro-Pérez ML, Gervasini G. Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease. EXCLI JOURNAL 2021; 20:698-708. [PMID: 34040498 PMCID: PMC8144539 DOI: 10.17179/excli2021-3408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022]
Abstract
Preclinical studies indicate that arachidonic acid (AA)-derived eicosanoids contribute to hyperglycemia-induced kidney injury. We aimed to determine whether plasma and/or urinary levels of dihydroxyeicosatrienoic (DHETs) and 20-hydroxyeicosatetraenoic (20-HETE) acids are associated with diabetic kidney disease (DKD). A total of 334 subjects (132 DKD patients and 202 non-diabetic individuals) were studied. Plasma levels of 11,12-DHET, 14,15-DHET and 20-HETE were measured by LC/MS/MS. Urinary 20-HETE concentrations were determined by immunoenzymatic assay. Subjects with normoalbuminuria had larger 20-HETE-to-creatinine urinary ratios (20-HETE/Cr) than those with micro and macroalbuminuria (p=0.012). Likewise, participants with eGFR>60 ml/min/1.73 m2 had higher plasma levels of 14,15-DHET (p=0.039) and 20-HETE/Cr ratios (p=0.007). Concentrations of 14,15-DHET, 11,12-DHET and 20-HETE/Cr were significantly lower in DKD patients. Median values for non-diabetic vs. DKD were, respectively, 493 (351.0-691.5) vs. 358 (260.5-522) ng/L, p=3e-5; 262 (183.5-356.0) vs. 202 (141.5-278.0) ng/L, p=1e-4 and 5.26 (1.68-11.65) vs. 2.53 (1.01-6.28) ng/mgCr, p=0.010. In addition, 20-HETE/Cr ratios were higher in patients with non-proteinuric DKD than in those with typical DKD (p=0.020). When only individuals with impaired filtration were considered, 14,15-DHET and 11,12-DHET levels were still higher in non-diabetic subjects (p=0.002 and p=0.006, respectively). Our results indicate that AA-derived eicosanoids may play a relevant role in DKD.
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Affiliation(s)
- Sonia Mota-Zamorano
- Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain
| | - Nicolás R Robles
- Service of Nephrology, Badajoz University Hospital, Badajoz, Spain
| | - Juan Lopez-Gomez
- Service of Clinical Analyses, Badajoz University Hospital, Badajoz, Spain
| | - Bárbara Cancho
- Service of Nephrology, Badajoz University Hospital, Badajoz, Spain
| | - Luz M González
- Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain
| | | | | | - Guillermo Gervasini
- Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain
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Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, Hu J, Fleming I, Wang DW. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther 2021; 6:94. [PMID: 33637672 PMCID: PMC7910446 DOI: 10.1038/s41392-020-00443-w] [Citation(s) in RCA: 567] [Impact Index Per Article: 141.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/04/2020] [Accepted: 10/15/2020] [Indexed: 01/31/2023] Open
Abstract
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
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Affiliation(s)
- Bei Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Lujin Wu
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jing Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Zheng Wen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jiong Hu
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
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Pidkovka N, Rachkevych O, Belkhiri A. Extrahepatic cytochrome P450 epoxygenases: pathophysiology and clinical significance in human gastrointestinal cancers. Oncotarget 2021; 12:379-391. [PMID: 33659048 PMCID: PMC7899545 DOI: 10.18632/oncotarget.27893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/01/2021] [Indexed: 12/29/2022] Open
Abstract
Cytochrome P450 (CYP) epoxygenases, a multi-gene superfamily of heme-containing enzymes, are commonly known to metabolize endogenous arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs). The role of CYPs is mostly studied in liver drugs metabolism, cardiac pathophysiology, and hypertension fields. Particularly, the biological functions of these enzymes have increasingly attracted a growing interest in cancer biology. Most published studies on CYPs in cancer have been limited to their role as drug metabolizing systems. The activity of these enzymes may affect drug pharmacokinetics and bioavailability as well as exogenous compounds turnover. Some CYP isoforms are selectively highly expressed in tumors, suggesting a potential mechanistic role in promoting resistance to chemotherapy. Majority of drugs elicit their effects in extrahepatic tissues whereby their metabolism can significantly determine treatment outcome. Nonetheless, the role of extrahepatic CYPs is not fully understood and targeting these enzymes as effective anti-cancer therapies are yet to be developed. This review article summarizes an up-to-date body of information from published studies on CYP enzymes expression levels and pathophysiological functions in human normal and malignant gastrointestinal (GI) tract tissues. Specifically, we reviewed and discussed the current research initiatives by emphasizing on the clinical significance and the pathological implication of CYPs in GI malignancies of esophagus, stomach, and colon.
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Affiliation(s)
| | - Olena Rachkevych
- Department of Obstetrics and Gynecology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Identifying the Dominant Contribution of Human Cytochrome P450 2J2 to the Metabolism of Rivaroxaban, an Oral Anticoagulant. Cardiovasc Drugs Ther 2021; 36:121-129. [PMID: 33411110 DOI: 10.1007/s10557-020-07129-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 11/25/2022]
Abstract
PURPOSE Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety. METHODS The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions. RESULTS Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions. CONCLUSION CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.
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Habieb MS, Dawood AA, Emara MM, Elhelbawy MG, Elhelbawy NG. The Human Genetic Variants CYP2J2 rs2280275 and EPHX2 rs751141 and Risk of Diabetic Nephropathy in Egyptian Type 2 Diabetic Patients. Appl Clin Genet 2020; 13:165-178. [PMID: 33239900 PMCID: PMC7682612 DOI: 10.2147/tacg.s281502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN), the primary driver of end-stage kidney disease, is a problem with serious consequences for society's health. Single nucleotide polymorphisms (SNPs) can define differences in susceptibility to DN and aid in development of personalized treatment. Giving the importance of epoxyeicosatrienoic acids (EETs) in kidney health, we aimed to study the association between two SNPs in the genes controlling synthesis and degradation of EETs (CYP2J2 rs2280275 and EPHX2 rs751141 respectively) and susceptibility of type 2 diabetes mellitus (T2DM) patients to develop DN. PATIENTS AND METHODS Two hundred subjects were enrolled and categorized into three groups: group I (80 T2DM patients with DN), group II (60 T2DM patients without DN) and group III (60 healthy controls). Urea, creatinine, albumin/creatinine ratio (ACR), and eGFR were measured for all participants. Genotyping of CYP2J2 rs2280275 and EPHX2 rs751141 was done by real time PCR. RESULTS There was no significant difference between the studied groups regarding CYP2J2 rs2280275. In contrast, EPHX2 rs751141 was associated with increased risk of DN under a dominant model (GG vs GA+AA: OR=0.375; 95% CI (0.19-0.75), P=0.006) in unadjusted model and after adjustment for age and sex (OR=0.440; 95% CI (0.21-0.92), P=0.029), recessive model (AA vs GG+GA: OR=0.195; 95% CI (0.05-0.74), P=0.017) and additive model (GA vs GG+AA): OR=0.195; 95% CI (0.05-0.74), P=0.017). CONCLUSION CYP2J2 rs2280275 was not associated with DN predisposition. However, EPHX2 rs751141 could be a genetic marker for development and progression of DN among Egyptian T2DM patients.
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Affiliation(s)
- Mona S Habieb
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt
| | - Ashraf A Dawood
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt
| | - Mahmoud M Emara
- Internal Medicine Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt
| | - Mohammad G Elhelbawy
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt
| | - Nesreen G Elhelbawy
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt
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Imig JD, Jankiewicz WK, Khan AH. Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture. Hypertension 2020; 76:3-15. [PMID: 32475311 PMCID: PMC7448548 DOI: 10.1161/hypertensionaha.120.13898] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.
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Affiliation(s)
- John D Imig
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
| | - Wojciech K Jankiewicz
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
| | - Abdul H Khan
- From the Department of Pharmacology and Toxicology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee
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Zhang Q, Yan G, Lei J, Chen Y, Wang T, Gong J, Zhou Y, Zhao H, Chen H, Zhou Y, Wu L, Zhang J, Zhang X, Wang J, Li Y. The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer. Mol Med 2020; 26:39. [PMID: 32375633 PMCID: PMC7201572 DOI: 10.1186/s10020-020-00174-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/24/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. METHODS Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. RESULTS SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. CONCLUSION Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.
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Affiliation(s)
- Qi Zhang
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Guifang Yan
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Juan Lei
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yu Chen
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Ting Wang
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Juan Gong
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yong Zhou
- Chongqing Weisiteng Biotech Translational Research Institute, Chongqing, China
| | - Huakan Zhao
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hao Chen
- Department of Medical Administration, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yu Zhou
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lei Wu
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiangang Zhang
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiao Zhang
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jingchun Wang
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yongsheng Li
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China.
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Association of CYP2J2 polymorphism with susceptibility to psoriasis in Turkish population: a case-control study. An Bras Dermatol 2020; 95:25-31. [PMID: 31902555 PMCID: PMC7058872 DOI: 10.1016/j.abd.2019.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 04/19/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Cytochrome P450 2J2 is mostly expressed in extrahepatic tissues; it metabolizes arachidonic acid to epoxyeicosatrienoic acids, with various cardio protective and anti-inflammatory effects. CYP2J2 polymorphism has been identified as a risk factor for cardiovascular diseases, but its association with psoriasis remains unknown. OBJECTIVE To evaluate CYP2J2 polymorphism as a risk factor for psoriasis in the Turkish population. METHODS There were 94 patients with psoriasis and 100 age- and sex-matched healthy controls included in the study. Detailed demographic and clinical characteristics were recorded, and Psoriasis Area and Severity Index (PASI) scores were calculated for psoriasis patients. Venous blood samples were collected from all the participants and CYP2J2 50G>T (rs890293) polymorphism was analyzed using polymerase chain reaction (PCR). RESULTS Both T allele and TT+GT genotype frequencies were increased in psoriasis vulgaris patients compared to the control group (p=0.024 and p=0.029 respectively, OR=2.82, 95% CI: 1.11-7.15) No association between CYP2J2 polymorphism and clinical features of psoriasis was identified. STUDY LIMITATIONS A limited number of patients were included in the study. CONCLUSION CYP2J2 50G>T (rs890293) polymorphism was associated with an increased risk for PsV in the Turkish population.
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Dos Santos LRB, Fleming I. Role of cytochrome P450-derived, polyunsaturated fatty acid mediators in diabetes and the metabolic syndrome. Prostaglandins Other Lipid Mediat 2019; 148:106407. [PMID: 31899373 DOI: 10.1016/j.prostaglandins.2019.106407] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 11/14/2019] [Accepted: 12/23/2019] [Indexed: 12/17/2022]
Abstract
Over the last decade, cases of metabolic syndrome and type II diabetes have increased exponentially. Exercise and ω-3 polyunsaturated fatty acid (PUFA)-enriched diets are usually prescribed but no therapy is effectively able to restore the impaired glucose metabolism, hypertension, and atherogenic dyslipidemia encountered by diabetic patients. PUFAs are metabolized by different enzymes into bioactive metabolites with anti- or pro-inflammatory activity. One important class of PUFA metabolizing enzymes are the cytochrome P450 (CYP) enzymes that can generate a series of bioactive products, many of which have been attributed protective/anti-inflammatory and insulin-sensitizing effects in animal models. PUFA epoxides are, however, further metabolized by the soluble epoxide hydrolase (sEH) to fatty acid diols. The biological actions of the latter are less well understood but while low concentrations may be biologically important, higher concentrations of diols derived from linoleic acid and docosahexaenoic acid have been linked with inflammation. One potential application for sEH inhibitors is in the treatment of diabetic retinopathy where sEH expression and activity is elevated as are levels of a diol of docosahexaenoic acid that can induce the destabilization of the retina vasculature.
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Affiliation(s)
- Laila R B Dos Santos
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) Partner Site Rhein-Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK) Partner Site Rhein-Main, Germany.
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Cytochrome P450 monooxygenase-mediated eicosanoid pathway: A potential mechanistic linkage between dietary fatty acid consumption and colon cancer risk. FOOD SCIENCE AND HUMAN WELLNESS 2019. [DOI: 10.1016/j.fshw.2019.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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Hausner EA, Elmore SA, Yang X. Overview of the Components of Cardiac Metabolism. Drug Metab Dispos 2019; 47:673-688. [PMID: 30967471 PMCID: PMC7333657 DOI: 10.1124/dmd.119.086611] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/26/2019] [Indexed: 12/20/2022] Open
Abstract
Metabolism in organs other than the liver and kidneys may play a significant role in how a specific organ responds to chemicals. The heart has metabolic capability for energy production and homeostasis. This homeostatic machinery can also process xenobiotics. Cardiac metabolism includes the expression of numerous organic anion transporters, organic cation transporters, organic carnitine (zwitterion) transporters, and ATP-binding cassette transporters. Expression and distribution of the transporters within the heart may vary, depending on the patient's age, disease, endocrine status, and various other factors. Several cytochrome P450 (P450) enzyme classes have been identified within the heart. The P450 hydroxylases and epoxygenases within the heart produce hydroxyeicosatetraneoic acids and epoxyeicosatrienoic acids, metabolites of arachidonic acid, which are critical in regulating homeostatic processes of the heart. The susceptibility of the cardiac P450 system to induction and inhibition from exogenous materials is an area of expanding knowledge, as are the metabolic processes of glucuronidation and sulfation in the heart. The susceptibility of various transcription factors and signaling pathways of the heart to disruption by xenobiotics is not fully characterized but is an area with implications for disruption of normal postnatal development, as well as modulation of adult cardiac health. There are knowledge gaps in the timelines of physiologic maturation and deterioration of cardiac metabolism. Cross-species characterization of cardiac-specific metabolism is needed for nonclinical work of optimum translational value to predict possible adverse effects, identify sensitive developmental windows for the design and conduct of informative nonclinical and clinical studies, and explore the possibilities of organ-specific therapeutics.
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Affiliation(s)
- Elizabeth A Hausner
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
| | - Susan A Elmore
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
| | - Xi Yang
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
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Liutkeviciene R, Vilkeviciute A, Botov R, Botova O, Buteikiene D, Kriauciuniene L. Associations between CYP2J2 (-76G>T) rs890293 polymorphism and age-related macular degeneration. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2019; 164:267-272. [PMID: 31132075 DOI: 10.5507/bp.2019.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/23/2019] [Indexed: 11/23/2022] Open
Abstract
Backgroung. Age-related macular degeneration (AMD) is a disease of the macula, which significantly affects the eyesight and leads to irreversible central vision loss. The etiopathogenesis of AMD is still not absolutely clear. It is thought that age-related macular degeneration has a multifactorial etiology, the development of which may be caused by interrelation of environmental with innate factors, while genetic factors also have an impact. Macular degenerative changes occur due to the formation of drusen, about 40% of which is lipids. As the CYP2J2 gene is involved in the metabolism of lipids, it was selected for investigation in this study. PURPOSE To determine the relation between early stage and exudative AMD and CYP2J2 (-76G>T) gene rs890293 polymorphism in a Lithuanian population. METHODS The study enrolled 204 patients with early AMD, 197 patients with exudative AMD and 198 healthy controls. Samples of DNA from peripheral white blood cells were purified using commercial kits. The genotyping was carried out using a real-time PCR method. RESULTS The CYP2J2 (-76G>T) rs890293 TT genotype in patients with early AMD was statistically significantly less frequent than in the control group: 0% vs. 2.5% (P=0.028). There were no significant differences in rs890293 gene polymorphisms between the exudative AMD and control groups. Also, the CYP2J2 (-76G>T) rs890293 TT genotype was statistically significantly less frequent in older early AMD patients (≥65 years) compared to control group persons (≥65 years): 0% vs. 5.4% (P=0.03). CONCLUSION The CYP2J2 (-76G>T) TT genotype may be associated with reduced manifestation of early stage AMD; therefore, a larger sample size is required for further analysis.
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Affiliation(s)
- Rasa Liutkeviciene
- Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009.,Department of Ophthalmology, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
| | - Alvita Vilkeviciute
- Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
| | - Roman Botov
- Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
| | - Olga Botova
- Department of Ophthalmology, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
| | - Dovile Buteikiene
- Department of Ophthalmology, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
| | - Loresa Kriauciuniene
- Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009.,Department of Ophthalmology, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, Lithuania, LT-50009
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Clermont V, Grangeon A, Barama A, Turgeon J, Lallier M, Malaise J, Michaud V. Activity and mRNA expression levels of selected cytochromes P450 in various sections of the human small intestine. Br J Clin Pharmacol 2019; 85:1367-1377. [PMID: 30817016 DOI: 10.1111/bcp.13908] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/30/2022] Open
Abstract
AIMS To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine. METHODS Tissue samples were obtained from 9 deceased subjects and intestinal sections (n = 10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real-time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid-jejunum) and ileum (proximal and mid-ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated liquid chromatography-tandem mass spectrometry assays. RESULTS Cytochrome P450 mRNA levels ranked as follows: CYP3A4 > CYP2C9 > CYP2C19 > CYP2J2 > CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from 1 region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activities were greater in proximal part of the small intestine with the jejunum showing the greatest drug-metabolism activity. Spearman's correlation analyses indicated that cytochrome P450 mRNA expressions and corresponding cytochrome P450 activities in the human intestine were moderately associated for CYP2C19, CYP2D6 and CYP4A11 (rs = 0.44-0.56). CONCLUSIONS Our study provides new and additional information on the expression and activities of selected cytochromes P450 in various sections of the human small intestine.
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Affiliation(s)
- Valérie Clermont
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Alexia Grangeon
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Azemi Barama
- Department of Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | - Jacques Turgeon
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Michel Lallier
- Department of Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | - Jacques Malaise
- Department of Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | - Veronique Michaud
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
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Kumar U A, Shariff M. Letter to the editor regarding "Role of cytochrome epoxygenase (CYP2J2) in the pathophysiology of coronary artery disease in South Indian Population.". Indian Heart J 2019; 71:174-175. [PMID: 31280833 PMCID: PMC6620410 DOI: 10.1016/j.ihj.2019.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/14/2019] [Indexed: 11/28/2022] Open
Affiliation(s)
- Ashish Kumar U
- Department of Critical Care Medicine, St. John's Medical College Hospital, Bangalore, Karnataka, 560034, India.
| | - Mariam Shariff
- Department of Critical Care Medicine, St. John's Medical College Hospital, Bangalore, Karnataka, 560034, India.
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Polonikov AV, Ponomarenko IV, Bykanova MA, Sirotina SS, Bocharova AV, Vagaytseva KV, Stepanov VA, Azarova IE, Churnosov MI, Solodilova MA. A comprehensive study revealed SNP-SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk. Hypertens Res 2018; 42:257-272. [PMID: 30518987 DOI: 10.1038/s41440-018-0142-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 06/18/2018] [Accepted: 07/12/2018] [Indexed: 11/09/2022]
Abstract
This study investigated whether common polymorphisms of cytochrome P450 2J2 (CYP2J2), a major enzyme that controls the biosynthesis of vasoactive epoxyeicosatrienoic acids, are collectively involved in the molecular basis of essential hypertension (EH). A total of 2314 unrelated Russian subjects from the Kursk (discovery sample: 913 EH patients and 645 controls) and Belgorod (replication sample: 345 EH patients and 411 controls) regions were recruited for this study. Eight single nucleotide polymorphisms (SNPs), including rs890293, rs11572182, rs10493270, rs1155002, rs2280275, rs7515289, rs11572325, and rs10889162, of CYP2J2 were genotyped using the MassARRAY 4 system and TaqMan-based assays. Significant associations were identified among the SNPs rs890293 (OR = 2.17, 95%CI 1.30-3.65), rs2280275 (OR = 1.59, 95%CI 1.10-2.37) and rs11572325 (OR = 1.89, 95%CI 1.22-2.95) and the risk of EH in females from the Kursk population. Sixteen CYP2J2 genotype combinations only showed significant associations with EH risk only in females. A common haplotype, T-T-G-C-C-C-T-A, increased the risk of EH in females. The bioinformatic analysis enabled identification of the SNPs that possess regulatory potential and/or are located within the binding sites for multiple transcription factors that play roles in the pathways involved in hypertension pathogenesis. Moreover, the polymorphisms rs890293, rs2280275, and rs11572325 were found to be significantly associated with hypertension risk in the Belgorod population. In conclusion, the rs2280275 and rs11572325 SNPs of CYP2J2 may be considered novel genetic markers of hypertension, at least in Russian women. However, sex-specific associations between CYP2J2 gene polymorphisms and hypertension require further investigation to clarify the specific genetic and/or environmental factors that are responsible for the increased disease susceptibility of women compared to that of men.
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Affiliation(s)
- Alexey V Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk, 305041, Russian Federation. .,Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, 305041, Russian Federation.
| | - Irina V Ponomarenko
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk, 305041, Russian Federation
| | - Marina A Bykanova
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, 305041, Russian Federation
| | - Svetlana S Sirotina
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk, 305041, Russian Federation
| | - Anna V Bocharova
- Evolutionary Genetics Laboratory, Research Institute of Medical Genetics, Tomsk National Medical Research Center, 10 Nabereznaya Ushaiki, Tomsk, 634050, Russian Federation
| | - Kseniya V Vagaytseva
- Evolutionary Genetics Laboratory, Research Institute of Medical Genetics, Tomsk National Medical Research Center, 10 Nabereznaya Ushaiki, Tomsk, 634050, Russian Federation
| | - Vadim A Stepanov
- Evolutionary Genetics Laboratory, Research Institute of Medical Genetics, Tomsk National Medical Research Center, 10 Nabereznaya Ushaiki, Tomsk, 634050, Russian Federation
| | - Iuliia E Azarova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, 305041, Russian Federation
| | - Mikhail I Churnosov
- Department of Medical Biological Disciplines, Belgorod State University, 85 Pobeda St., Belgorod, 308015, Russian Federation
| | - Maria A Solodilova
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk, 305041, Russian Federation
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Abstract
Therapeutics for arachidonic acid pathways began with the development of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX). The enzymatic pathways and arachidonic acid metabolites and respective receptors have been successfully targeted and therapeutics developed for pain, inflammation, pulmonary and cardiovascular diseases. These drugs target the COX and lipoxygenase pathways but not the third branch for arachidonic acid metabolism, the cytochrome P450 (CYP) pathway. Small molecule compounds targeting enzymes and CYP epoxy-fatty acid metabolites have evolved rapidly over the last two decades. These therapeutics have primarily focused on inhibiting soluble epoxide hydrolase (sEH) or agonist mimetics for epoxyeicosatrienoic acids (EET). Based on preclinical animal model studies and human studies, major therapeutic indications for these sEH inhibitors and EET mimics/analogs are renal and cardiovascular diseases. Novel small molecules that inhibit sEH have advanced to human clinical trials and demonstrate promise for cardiovascular diseases. Challenges remain for sEH inhibitor and EET analog drug development; however, there is a high likelihood that a drug that acts on this third branch of arachidonic acid metabolism will be utilized to treat a cardiovascular or kidney disease in the next decade.
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Affiliation(s)
- John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Tantray JA, Reddy KP, Jamil K, Yerra SK. Role of cytochrome epoxygenase (CYP2J2) in the pathophysiology of coronary artery disease in South Indian population. Indian Heart J 2018; 71:60-64. [PMID: 31000184 PMCID: PMC6477124 DOI: 10.1016/j.ihj.2018.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/29/2018] [Accepted: 11/05/2018] [Indexed: 12/27/2022] Open
Abstract
Background The cytochrome P-450 2J2 (CYP2J2) is known to be one of the major enzymes of epoxygenase pathway of arachidonic acid in extrahepatic tissues, which produces series of regioisomeric cis-epoxyeicosatrienoic acids (EETs) such as 5,6-, 8,9-, 11,12-, and 14,15-EETs. In the present study, we analyzed the impact of a genetic variant in CYP2J2 on coronary artery disease (CAD) in the Telangana region of Indian population. Material and methods The case–control study consisted of 100 CAD cases and 110 healthy controls. The deoxyribonucleic acid was extracted using the salting out method. Genotyping and gene expression was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time-PCR methods. Results In the present study, the percentage of smokers, alcoholics, hypertensive patients, and diabetics was high. Increase in fasting glucose, urea, creatinine, fasting triglycerides, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), total cholesterol/high-density lipoprotein (TC/HDL), LDL/HDL, homocysteine, and C-reactive protein levels were significantly higher in patients with CAD than in controls (p < 0.001). CYP2J2 G-50T was associated with CAD (p = 0.04). The mRNA expression of CYP2J2 showed altered gene expression in this study among CAD patients in comparison with control (p = 0.01). Conclusions A functionally relevant polymorphism of the CYP2J2 gene was independently associated with an increased risk of CAD.
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Affiliation(s)
- Javeed Ahmad Tantray
- Department of Zoology, Osmania University Hyderabad, Telangana, India; Dept. of Genetics, Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, Hyderabad-500004, Telangana, India.
| | - K Pratap Reddy
- Department of Zoology, Osmania University Hyderabad, Telangana, India.
| | - Kaiser Jamil
- Dept. of Genetics, Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, Hyderabad-500004, Telangana, India.
| | - Shiva Kumar Yerra
- Department of Cardiology, Mahavir Hospital and Research Centre Hyderabad, Telangana, India.
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Fava C, Bonafini S. Eicosanoids via CYP450 and cardiovascular disease: Hints from genetic and nutrition studies. Prostaglandins Other Lipid Mediat 2018; 139:41-47. [DOI: 10.1016/j.prostaglandins.2018.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/25/2018] [Accepted: 10/03/2018] [Indexed: 01/11/2023]
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Cao P, Zhao Q, Shao Y, Yang H, Jin T, Li B, Li H. Genetic polymorphisms of the drug-metabolizing enzyme CYP2J2 in a Tibetan population. Medicine (Baltimore) 2018; 97:e12579. [PMID: 30290621 PMCID: PMC6200477 DOI: 10.1097/md.0000000000012579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
As an important metabolic enzyme, it is necessary to investigate the genetic polymorphisms of CYP2J2 among healthy Tibetan individuals. Genetic polymorphisms of CYP2J2 could affect enzyme activity and lead to differences among individual responses to drugs.We sequenced the whole gene of CYP2J2 in 100 unrelated, healthy Tibetan volunteers from the Tibet Autonomous Region and screened for genetic variants in the promoters, introns, exons, and the 3'-UTR regions.We detected 4 novel genetic polymorphisms of the CYP2J2 gene. The allelic frequencies of CYP2D6*1 and *7 were 0.955 and 0.045, respectively. CYP2D6*1/*7 decreased the activity of CYP2J2 and was expressed in 9% of the sample population.Our results provided basic data about CYP2J2 polymorphisms in a Tibetan population, suggested that the enzymatic activities of CYP2J2 might be different within the ethnic group, and offered a theoretical basis for individualized medical treatment and drug genomics studies.
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Affiliation(s)
| | - Qian Zhao
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University
| | - Yuan Shao
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University
| | - Hua Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, College of Life Sciences, Northwest University, Xi’an
| | - Tianbo Jin
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, College of Life Sciences, Northwest University, Xi’an
- School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Baiya Li
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University
| | - Honghui Li
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University
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Zhao Q, Huang J, Wang D, Chen L, Sun D, Zhao C. Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling. J Mol Cell Cardiol 2018; 123:118-127. [DOI: 10.1016/j.yjmcc.2018.08.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 08/17/2018] [Accepted: 08/29/2018] [Indexed: 12/23/2022]
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Xie X, Jiang J, Ye W, Chen R, Deng Y, Wen J. Sp1, Instead of AhR, Regulates the Basal Transcription of Porcine CYP1A1 at the Proximal Promoter. Front Pharmacol 2018; 9:927. [PMID: 30174605 PMCID: PMC6107784 DOI: 10.3389/fphar.2018.00927] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 07/30/2018] [Indexed: 12/31/2022] Open
Abstract
Pigs are commonly used as an animal model to evaluate the toxic effects of exogenous compounds. Cytochrome P450 1A1 (CYP1A1) metabolizes numerous exogenous compounds and is abundantly expressed in the liver, kidneys, and intestines. The high amino acid similarity between human and porcine CYP1A1 indicates that they probably have the same metabolic characteristics. Therefore, understanding the regulatory mechanism of CYP1A1 expression in pigs is particularly important for predicting the toxicology and metabolic kinetics of exogenous chemicals. Currently, the transcriptional regulation of porcine CYP1A1 has rarely been studied, especially regarding basal transcription. In this study, we first confirmed that the key regulatory elements of porcine CYP1A1 basal transactivation are in the proximal promoter region using promoter truncation analysis via a dual luciferase assay in a porcine kidney cell line LLC-PK1. Two overlapping cis-elements, the xenobiotic response element (XRE) and GC box, in this proximal region potentially play key roles in the basal transactivation of porcine CYP1A1. Furthermore, using electrophoretic mobility shift assay and chromatin immunoprecipitation, the GC box binding protein Sp1 was confirmed to bind to the proximal promoter of porcine CYP1A1, instead of AhR, the XRE binding protein. In LLC-PK1 cells, by knocking down either Sp1 or AhR, the expression of porcine CYP1A1 at the mRNA level and protein level was significantly downregulated, suggesting both proteins are important for porcine CYP1A1 expression. However, promoter activity analysis in LLC-PK1 cells treated with an AhR agonist and antagonist confirmed that AhR does not participate in the basal regulation of porcine CYP1A1 at the proximal promoter. In conclusion, our study revealed that the proximal promoter is the key regulatory region for porcine CYP1A1 basal expression. Although AhR plays an important role in the transactivation of porcine CYP1A1 expression, the key determinant transcription factor for its basal transactivation is Sp1 at the proximal promoter of porcine CYP1A1.
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Affiliation(s)
- Xuan Xie
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
| | - Jun Jiang
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
| | - Wenchu Ye
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
| | - Ruohong Chen
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
| | - Yiqun Deng
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
| | - Jikai Wen
- Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.,Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, China
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Kang X, Shi H, Zhang L, Wang Y, Zhang T, Han M, Chen C, Wang H. Genetic polymorphisms of CYP2S1, CYP2J2 and CYP2R1 genes in three Chinese populations: Han, Tibetan and Uighur. Pharmacogenomics 2018; 19:961-977. [PMID: 30019995 DOI: 10.2217/pgs-2018-0063] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM Cytochrome P450 enzymes CYP2S1, CYP2J2 and CYP2R1 are of interest due to their unknown enzymatic function and disease-specific expression property. The aim of this study was to investigate the genetic variations of CYP2S1, CYP2J2 and CYP2R1 genes, and their polymorphic distribution in different Chinese populations. MATERIALS & METHODS All of the exons, exon-intron boundaries and 1 kb 5'-flanking region of the three genes were sequenced in 150 Chinese subjects. RESULTS There were 21, 15 and nine genetic variants identified in CYP2S1, CYP2J2 and CYP2R1 genes, respectively. The genetic polymorphisms of CYP2S1 and CYP2J2 showed significant difference. Thr353Ala variant in CYP2S1 protein was predicted to be consistently damaged. The hydrogen bond interactions were decreased in two mutants: Thr353Ala and Cys372Ser. -177C >T in CYP2S1 affected transcription factor EGR1 binding site. CONCLUSION This study highlights the importance of genetic polymorphism information on the CYP2S1, CYP2J2 and CYP2R1 genes in Chinese populations.
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Affiliation(s)
- Xing Kang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Hailong Shi
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang, PR China
| | - Lirong Zhang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Yanxia Wang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Tingting Zhang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Min Han
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Chao Chen
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
| | - Huijuan Wang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China
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Solanki M, Pointon A, Jones B, Herbert K. Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity. Drug Metab Dispos 2018; 46:1053-1065. [PMID: 29695613 DOI: 10.1124/dmd.117.078964] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 04/19/2018] [Indexed: 02/13/2025] Open
Abstract
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
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Affiliation(s)
- Meetal Solanki
- Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield Hospital, Leicester (M.S., K.H.), and Safety and ADME Translational Sciences Department, Drug Safety and Metabolism (A.P.), and DMPK, Oncology, IMED Biotech Unit (B.J.), AstraZeneca, Cambridge, United Kingdom
| | - Amy Pointon
- Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield Hospital, Leicester (M.S., K.H.), and Safety and ADME Translational Sciences Department, Drug Safety and Metabolism (A.P.), and DMPK, Oncology, IMED Biotech Unit (B.J.), AstraZeneca, Cambridge, United Kingdom
| | - Barry Jones
- Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield Hospital, Leicester (M.S., K.H.), and Safety and ADME Translational Sciences Department, Drug Safety and Metabolism (A.P.), and DMPK, Oncology, IMED Biotech Unit (B.J.), AstraZeneca, Cambridge, United Kingdom
| | - Karl Herbert
- Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield Hospital, Leicester (M.S., K.H.), and Safety and ADME Translational Sciences Department, Drug Safety and Metabolism (A.P.), and DMPK, Oncology, IMED Biotech Unit (B.J.), AstraZeneca, Cambridge, United Kingdom
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Lafite P, André F, Graves JP, Zeldin DC, Dansette PM, Mansuy D. Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2. Int J Mol Sci 2018; 19:ijms19072066. [PMID: 30012976 PMCID: PMC6073854 DOI: 10.3390/ijms19072066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 07/06/2018] [Accepted: 07/13/2018] [Indexed: 01/10/2023] Open
Abstract
The influence of Arginine 117 of human cytochrome P450 2J2 in the recognition of ebastine and a series of terfenadone derivatives was studied by site-directed mutagenesis. R117K, R117E, and R117L mutants were produced, and the behavior of these mutants in the hydroxylation of ebastine and terfenadone derivatives was compared to that of wild-type CYP2J2. The data clearly showed the importance of the formation of a hydrogen bond between R117 and the keto group of these substrates. The data were interpreted on the basis of 3D homology models of the mutants and of dynamic docking of the substrates in their active site. These modeling studies also suggested the existence of a R117-E222 salt bridge between helices B’ and F that would be important for maintaining the overall folding of CYP2J2.
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Affiliation(s)
- Pierre Lafite
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, 75270 Paris CEDEX 06, France.
| | - François André
- Institute for Integrative Biology of the Cell (I2BC), DRF/Joliot/SB2SM, CEA, CNRS, Université Paris-Saclay, F-91198 Gif-sur-Yvette CEDEX, France.
| | - Joan P Graves
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA.
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA.
| | - Patrick M Dansette
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, 75270 Paris CEDEX 06, France.
| | - Daniel Mansuy
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, 75270 Paris CEDEX 06, France.
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Abstract
Globally, cardiovascular diseases (CVDs) are the number one cause of mortality. Approximately 18 million people died from CVDs in 2015, representing more than 30% of all global deaths. New diagnostic tools and therapies are eagerly required to decrease the prevalence of CVDs related to mortality and/or risk factors leading to CVDs. Oxylipins are a group of metabolites, generated via oxygenation of polyunsaturated fatty acids that are involved in inflammation, immunity, and vascular functions, etc. Thus far, over 100 oxylipins have been identified, and have overlapping and interconnected roles. Important CVD pathologies such as hyperlipidemia, hypertension, thrombosis, hemostasis and diabetes have been linked to abnormal oxylipin signaling. Oxylipins represent a new era of risk markers and/or therapeutic targets in several diseases including CVDs. The role of many oxylipins in the progression or regression in CVD, however, is still not fully understood. An increased knowledge of the role of these oxygenated polyunsaturated fatty acids in cardiovascular dysfunctions or CVDs including hypertension could possibly lead to the development of biomarkers for the detection and their treatment in the future.
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Association of CYP3A5, CYP2C8, and ABCB1 Polymorphisms With Early Renal Injury in Chinese Liver Transplant Recipients Receiving Tacrolimus. Transplant Proc 2018; 50:3258-3265. [PMID: 30577195 DOI: 10.1016/j.transproceed.2018.06.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/18/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND The purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus. METHODS CYP3A5, ABCB1, and CYP2C8 polymorphisms were genotyped in the Chinese liver transplant recipients in the study receiving tacrolimus for at least 2 years by polymerase chain reaction and high-resolution melting method. Serum cystatin C and urine microprotein (α1-microglobulin, microalbumin, transferrin, and immunoglobulin) of liver transplant recipients were used to determine both the status of early renal injury and the lesion part. RESULTS We documented 3 genotypes of CYP3A5 and ABCB1 and only 2 genotypes of CYP2C8 in our cohort. The levels of cystatin C and all 4 indicators of the urine microprotein in the recipient group were significantly higher than those in the control group (P < .05). The concentrations of transferrin differed significantly in each CYP3A5 genotype group (P < .05). Based on diverse CYP2C8 genotypes, we divided all the recipients into 2 groups: CYP2C8*1*1 group and CYP2C8*3*1 group. The concentrations of α1-microglobulin and cystatin C differed significantly between the 2 groups (P < .05). For CYP2C8*3, the positive predictive value is 68.5% and negative predictive value is 70.2%. For CYP3A5*3, the positive predictive value is 55.3% and negative predictive value is 60.4%. CONCLUSIONS CYP2C8*3 and CYP3A5*3 appear to be predictive of risk of tacrolimus-induced early renal impairment. CYP3A5*3 was associated with the risk of early renal glomerular lesion, while CYP2C8*3 was associated with the risk of the tubulointerstitial injury. ABCB1 polymorphisms (both C3435T and C1236T) were not associated with the early renal injury in liver transplant recipients.
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