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McCann S, Helfer VE, Balevic SJ, Hornik CD, Goldstein SL, Autmizguine J, Meyer M, Al-Uzri A, Anderson SG, Payne EH, Turdalieva S, Gonzalez D. Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants. J Clin Pharmacol 2024; 64:963-974. [PMID: 38545761 PMCID: PMC11286355 DOI: 10.1002/jcph.2434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/04/2024] [Indexed: 07/30/2024]
Abstract
Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.
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Affiliation(s)
- Sean McCann
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The Universiy of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Victória E. Helfer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The Universiy of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Stephen J. Balevic
- Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
| | - Chi D. Hornik
- Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
| | | | - Julie Autmizguine
- Department of Pediatrics, Center Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
| | - Marisa Meyer
- Critical Care Medicine, Nemours Children’s Hospital, Delaware, Wilmington, DE, USA
| | - Amira Al-Uzri
- Oregon Health and Science University, Portland, OR, USA
| | | | | | | | - Daniel Gonzalez
- Duke Clinical Research Institute, Durham, NC, USA
- Division of Clinical Pharmacology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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Ferrari E, Cornali C, Fiorindi A, Agosti E, Gallone S, Rubino E, Ponzio F, Fontanella MM, De Maria L. Cigarette Smoking and Intracranial Aneurysms: A Pilot Analysis of SNPs in the CYP2A6 Gene in the Italian Population. World Neurosurg 2023; 179:e492-e499. [PMID: 37689358 DOI: 10.1016/j.wneu.2023.08.128] [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: 08/02/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND Cigarette smoking is a modifiable risk factor associated with formation and rupture of intracranial aneurysms (IAs). Cytochrome P450 2A6 (CYP2A6) is the main enzyme implied in catabolism of nicotine and xenobiotics, giving rise to oxidative stress products. Our study investigated the associations between specific single-nucleotide polymorphisms (SNPs) in the CYP2A6 gene and the presence of sporadic IAs in a cluster of Italian patients, as well as their rupture regarding cigarette smoking habit. METHODS Three hundred and thirty-one Italian patients with sporadic IAs were recruited in a single institution. We recorded data on clinical onset with subarachnoid hemorrhage (SAH) and smoking habit. Genetic analysis was performed with a standard procedure on peripheral blood samples: CYP2A6 ∗1B2, CYP2A6 ∗2, and CYP2A6 ∗14 SNPs were analyzed in the study group along with 150 healthy control subjects. Statistical analysis was conducted according to genetic association study guidelines. RESULTS In the patient cohort, the frequency of aSAH was significantly higher in current smokers (P < 0.001; OR=17.45), regardless of the pattern of CYP2A6 SNPs. There was a correlation between IA rupture and cigarette smoking in patients with the heterozygous CYP2A6 ∗1B2 allele (P < 0.001; OR=15.47). All patients carrying the heterozygous CYP2A6 ∗14 allele had an aSAH event (100%), regardless of smoking habit, although this correlation was not statistically significant (P = 1). CONCLUSIONS According to our findings, a cigarette smoker carrying a fully active CYP2A6 enzyme (heterozygous ∗1B2 allele) may have an increased risk of IA rupture compared to those with functionally less active variants: further investigation on a larger sample is needed to verify this result. The role of the heterozygous CYP2A6 ∗14 allele in aSAH is yet to be clarified.
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Affiliation(s)
- Erika Ferrari
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Claudio Cornali
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Alessandro Fiorindi
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Edoardo Agosti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Salvatore Gallone
- Department of Neuroscience "Rita Levi Montalcini", University of Torino, Turin, Italy
| | - Elisa Rubino
- Department of Neuroscience "Rita Levi Montalcini", University of Torino, Turin, Italy
| | - Francesco Ponzio
- Interuniversity Department of Regional and Urban Studies and Planning, Politecnico di Torino, Turin, Italy
| | - Marco Maria Fontanella
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Lucio De Maria
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
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Luo Y, Liu JY. Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer. Front Pharmacol 2020; 11:580897. [PMID: 33192522 PMCID: PMC7658919 DOI: 10.3389/fphar.2020.580897] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
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Affiliation(s)
- Ying Luo
- Department of Clinical Laboratory, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Jun-Yan Liu
- Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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4
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Farra C, Assaf N, Karaky N, Diab S, Zaatari G, Cortas N, Daher RT. Association between CYP2A6 genotypes and smoking behavior in Lebanese smokers. Meta Gene 2020. [DOI: 10.1016/j.mgene.2019.100616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Hsieh CJ, Sun M, Osborne G, Ricker K, Tsai FC, Li K, Tomar R, Phuong J, Schmitz R, Sandy MS. Cancer Hazard Identification Integrating Human Variability: The Case of Coumarin. Int J Toxicol 2019; 38:501-552. [PMID: 31845612 DOI: 10.1177/1091581819884544] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Coumarin is a naturally occurring sweet-smelling benzopyrone that may be extracted from plants or synthesized for commercial uses. Its uses include as a flavoring agent, fragrance enhancer, and odor-masking additive. We reviewed and evaluated the scientific evidence on the carcinogenicity of coumarin, integrating information from carcinogenicity studies in animals with mechanistic and other relevant data, including data from toxicogenomic, genotoxicity, and metabolism studies, and studies of human variability of a key enzyme, CYP2A6. Increases in tumors were observed in multiple studies in rats and mice in multiple tissues. Our functional pathway analysis identified several common cancer-related biological processes/pathways affected by coumarin in rat liver following in vivo exposure and in human primary hepatocytes exposed in vitro. When coumarin 7-hydroxylation by CYP2A6 is compromised, this can lead to a shift in metabolism to the 3,4-epoxidation pathway and increased generation of electrophilic metabolites. Mechanistic data align with 3 key characteristics of carcinogens, namely formation of electrophilic metabolites, genotoxicity, and induction of oxidative stress. Considerations of metabolism, human variability in CYP2A6 activity, and coumarin hepatotoxicity in susceptible individuals provide additional support for carcinogenicity concern. Our analysis illustrates the importance of integrating information on human variability in the cancer hazard identification process.
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Affiliation(s)
- ChingYi Jennifer Hsieh
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Meng Sun
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Gwendolyn Osborne
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Karin Ricker
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Feng C Tsai
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Kate Li
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Rajpal Tomar
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA.,Retired
| | - Jimmy Phuong
- Department of Biomedical and Health Informatics, University of Washington, Seattle, WA, USA
| | - Rose Schmitz
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
| | - Martha S Sandy
- Office of Environmental Health Hazard Assessment, CalEPA, Sacramento and Oakland, CA, USA
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Elfaki I, Mir R, Almutairi FM, Duhier FMA. Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis. Asian Pac J Cancer Prev 2018; 19:2057-2070. [PMID: 30139042 PMCID: PMC6171375 DOI: 10.22034/apjcp.2018.19.8.2057] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.
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Affiliation(s)
- Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Kingdom of Saudi Arabia.
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Soeroso NN, Zain-Hamid R, Sinaga BYM, Sadewa AH, Syafiuddin T, Syahruddin E, Tann G, Mutiara E. Genetic Polymorphism of CYP2A6 and Its Relationship with Nicotine Metabolism in Male Bataknese Smokers Suffered from Lung Cancer in Indonesia. Open Access Maced J Med Sci 2018; 6:1199-1205. [PMID: 30087722 PMCID: PMC6062282 DOI: 10.3889/oamjms.2018.259] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/22/2018] [Accepted: 05/25/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cytochrome P450 2A6 (CYP2A6) is known as an enzyme which is responsible for the metabolism of chemical compounds. AIM This study aimed to analyse the relationship between CYP2A6 gene polymorphism with nicotine metabolism rates and lung cancer incidence among smokers of Batak ethnic group in Indonesia. METHODS This study was a case-control study involving 140 research subjects through a purposive sampling technique from three hospitals in Medan, Indonesia. An examination of nicotine metabolism rates was conducted for all subjects using the 3HC/cotinine ratio parameter with LC-MS/MS technique. The examination of the CYP2A6 gene was performed with PCR-RFLP. Data were analysed with Conditional Logistic Regression test using Epi Info 7.0 software. RESULTS The allele frequencies of CYP2A6*1A, CYP2A6*1B, and CYP2A6*4A found were 44.3%, 48.9%, and 6.8%, respectively. The *1B allele showed the highest metabolism rate. It is found that slow metabolizer individuals were 5.49 times more likely to develop lung cancer (P = 0.01, 95%CI 1.2-24.8). CONCLUSION Among the Bataknese smokers studied, the CYP2A6*1B allele was found to be the most common allele and showed the highest rate of nicotine metabolism. However, the results show the insignificant relationship among CYP2A6 genetic polymorphism, nicotine metabolism, and lung cancer incidence.
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Affiliation(s)
- Noni Novisari Soeroso
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
| | - Rozaimah Zain-Hamid
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
| | - Bintang Y M Sinaga
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
| | - Ahmad Hamim Sadewa
- Department of Biochemistry, Faculty of Medicine, Gadjah Mada University, Jl. Farmako Sekip Utara, Yogyakarta 55281, Indonesia
| | - Tamsil Syafiuddin
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
| | - Elisna Syahruddin
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Jl. Persahabatan Raya No.1, Jakarta 13230, Indonesia
| | - Gino Tann
- Department of Clinical Pathology, Faculty of Medicine, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
| | - Erna Mutiara
- Department of Biostatistics, Faculty of Public Health, University of Sumatera Utara, Jl. Dr Mansyur No.5 Medan 20155, Indonesia
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8
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Ezzeldin N, El-Lebedy D, Darwish A, El Bastawisy A, Abd Elaziz SH, Hassan MM, Saad-Hussein A. Association of genetic polymorphisms CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 with tobacco-induced lung Cancer: case-control study in an Egyptian population. BMC Cancer 2018; 18:525. [PMID: 29724170 PMCID: PMC5934827 DOI: 10.1186/s12885-018-4342-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 04/08/2018] [Indexed: 11/10/2022] Open
Abstract
Background Several studies have reported the role of CYP2A6 genetic polymorphisms in smoking and lung cancer risk with some contradictory results in different populations. The purpose of the current study is to assess the contribution of the CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 gene polymorphisms and tobacco smoking in the risk of lung cancer in an Egyptian population. Methods A case-control study was conducted on 150 lung cancer cases and 150 controls. All subjects were subjected to blood sampling for Extraction of genomic DNA and Genotyping of the CYP2A6 gene SNPs (CYP2A6*2 (1799 T > A) rs1801272 and CYP2A6*9 (− 48 T > G) rs28399433 by Real time PCR. Results AC and CC genotypes were detected in CYP2A6*9; and AT genotype in CYP2A6*2. The frequency of CYP2A6*2 and CYP2A6*9 were 0.7% and 3.7% respectively in the studied Egyptian population. All cancer cases with slow metabolizer variants were NSCLC. Non-smokers represented 71.4% of the CYP2A6 variants. There was no statistical significant association between risk of lung cancer, smoking habits, heaviness of smoking and the different polymorphisms of CYP2A6 genotypes. Conclusion The frequency of slow metabolizers CYP2A6*2 and CYP2A6*9 are poor in the studied Egyptian population. Our findings did not suggest any association between CYP2A6 genotypes and risk of lung cancer.
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Affiliation(s)
- Nada Ezzeldin
- Chest Diseases, National Research Center, Cairo, Egypt
| | | | - Amira Darwish
- Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt. .,National Cancer Institute (NCI), Fom-Elkhalig Square, P.O.Box: 11796, Cairo, Egypt.
| | - Ahmed El Bastawisy
- Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | | | | | - Amal Saad-Hussein
- Environmental Health & Preventive Medicine, National Research Center, Cairo, Egypt
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9
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Tanner JA, Tyndale RF. Variation in CYP2A6 Activity and Personalized Medicine. J Pers Med 2017; 7:jpm7040018. [PMID: 29194389 PMCID: PMC5748630 DOI: 10.3390/jpm7040018] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 11/17/2017] [Accepted: 11/27/2017] [Indexed: 12/16/2022] Open
Abstract
The cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several clinically relevant substrates, including nicotine-the primary psychoactive component in cigarette smoke. The gene that encodes the CYP2A6 enzyme is highly polymorphic, resulting in extensive interindividual variation in CYP2A6 enzyme activity and the rate of metabolism of nicotine and other CYP2A6 substrates including cotinine, tegafur, letrozole, efavirenz, valproic acid, pilocarpine, artemisinin, artesunate, SM-12502, caffeine, and tyrosol. CYP2A6 expression and activity are also impacted by non-genetic factors, including induction or inhibition by pharmacological, endogenous, and dietary substances, as well as age-related changes, or interactions with other hepatic enzymes, co-enzymes, and co-factors. As variation in CYP2A6 activity is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics, CYP2A6 expression and enzyme activity is an important clinical consideration. This review will discuss sources of variation in CYP2A6 enzyme activity, with a focus on the impact of CYP2A6 genetic variation on metabolism of the CYP2A6 substrates.
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Affiliation(s)
- Julie-Anne Tanner
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada.
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Rachel F Tyndale
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada.
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
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Yang L, Zou S, Shu C, Song Y, Sun YK, Zhang W, Zhou A, Yuan X, Yang Y, Hu S. CYP2A6 Polymorphisms Associate with Outcomes of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients. GENOMICS PROTEOMICS & BIOINFORMATICS 2017; 15:255-262. [PMID: 28811232 PMCID: PMC5582793 DOI: 10.1016/j.gpb.2016.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 11/21/2016] [Accepted: 11/29/2016] [Indexed: 11/17/2022]
Abstract
Gastric carcinoma is a heterogeneous malignant disease involving genetic factors. To identify predictive markers for gastric cancer treatment in Chinese patients, we evaluated the association between polymorphisms of the gene encoding cytochrome P450 2A6 (CYP2A6) and outcomes of S-1 plus oxaliplatin (SOX) chemotherapy treatment. Clinical data on 60 consecutive gastric cancer patients receiving SOX regimen were collected prospectively. We sequenced all exons of CYP2A6 and a total of 22 different polymorphisms were detected in the present study. Comprehensive analyses of these genetic polymorphisms were performed to determine their association with both safety and efficacy of SOX regimen. Our results showed that polymorphisms of CYP2A6 were associated with the safety and efficacy of SOX treatment. Among them, missense mutations CYP2A6 rs60823196 and rs138978736 could be possible risk factors (P < 0.05) for severe diarrhea induced by SOX, whereas CYP2A6 rs138978736 could be a conceivable predictor for overall survival of patients treated with SOX adjuvant chemotherapy. Further large-scale randomized prospective studies are warranted to confirm these findings.
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Affiliation(s)
- Lin Yang
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Shanshan Zou
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Chang Shu
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yan Song
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen Zhang
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinghua Yuan
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yi Yang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Songnian Hu
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
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López-Flores LA, Pérez-Rubio G, Falfán-Valencia R. Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction. EXCLI JOURNAL 2017; 16:174-196. [PMID: 28507465 PMCID: PMC5427481 DOI: 10.17179/excli2016-847] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/13/2017] [Indexed: 01/08/2023]
Abstract
Tobacco consumption has become a major public health issue, which has motivated studies to identify and understand the biological processes involved in the smoking behavior for prevention and smoking cessation treatments. CYP2A6 has been identified as the main gene that codifies the enzyme that metabolizes nicotine. Many alleles have been identified after the discovery of CYP2A6, suggesting a wide interethnic variability and a diverse smoking behavior of the allele carrying individuals. The main purpose of this review is to update and highlight the effects of the CYP2A6 gene variability related to tobacco consumption reported from diverse human populations. The review further aims to consider CYP2A6 in future studies as a possible genetic marker for the prevention and treatment of nicotine addiction. Therefore, we analyzed several population studies and their importance at addressing and characterizing a population using specific parameters. Our efforts may contribute to a personalized system for detecting, preventing and treating populations at a higher risk of smoking to avoid diseases related to tobacco consumption.
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Hosono H, Kumondai M, Maekawa M, Yamaguchi H, Mano N, Oda A, Hirasawa N, Hiratsuka M. Functional Characterization of 34 CYP2A6 Allelic Variants by Assessment of Nicotine C-Oxidation and Coumarin 7-Hydroxylation Activities. Drug Metab Dispos 2017; 45:279-285. [PMID: 27974382 DOI: 10.1124/dmd.116.073494] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/13/2016] [Indexed: 11/22/2022] Open
Abstract
CYP2A6, a member of the cytochrome P450 (P450) family, is one of the enzymes responsible for the metabolism of therapeutic drugs and such tobacco components as nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and N-nitrosodiethylamine. Genetic polymorphisms in CYP2A6 are associated with individual variation in smoking behavior, drug toxicities, and the risk of developing several cancers. In this study, we conducted an in vitro analysis of 34 allelic variants of CYP2A6 using nicotine and coumarin as representative CYP2A6 substrates. These variant CYP2A6 proteins were heterologously expressed in 293FT cells, and their enzymatic activities were assessed on the basis of nicotine C-oxidation and coumarin 7-hydroxylation activities. Among the 34 CYP2A6 variants, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.10, CYP2A6.26, CYP2A6.36, and CYP2A6.37 exhibited no enzymatic activity, whereas 14 other variants exhibited markedly reduced activity toward both nicotine and coumarin. These comprehensive in vitro findings may provide useful insight into individual differences in smoking behavior, drug efficacy, and cancer susceptibility.
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Affiliation(s)
- Hiroki Hosono
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Masaki Kumondai
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Masamitsu Maekawa
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Hiroaki Yamaguchi
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Nariyasu Mano
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Akifumi Oda
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Noriyasu Hirasawa
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
| | - Masahiro Hiratsuka
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (H.H., M.K., N.H., M.H.), Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M.), Department of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (A.O.)
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Kumondai M, Hosono H, Orikasa K, Arai Y, Arai T, Sugimura H, Ozono S, Sugiyama T, Takayama T, Sasaki T, Hirasawa N, Hiratsuka M. Genetic Polymorphisms of CYP2A6 in a Case-Control Study on Bladder Cancer in Japanese Smokers. Biol Pharm Bull 2016; 39:84-89. [PMID: 26725431 DOI: 10.1248/bpb.b15-00604] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Several of the procarcinogens inhaled in tobacco smoke, the primary risk factor for bladder cancer, are activated by CYP2A6. The association between the whole-gene deletion of CYP2A6 (CYP2A6*4) and a reduced risk of bladder cancer was suggested in Chinese Han smokers. However, there is no evidence for association between the risk of bladder cancer and CYP2A6 genotypes in the Japanese population. Using genomic DNA from smokers of the Japanese population (163 bladder cancer patients and 116 controls), we conducted a case-control study to assess the association between CYP2A6 polymorphisms and the risk of bladder cancer. Determination of CYP2A6 genotypes was carried out by amplifying each exon of CYP2A6 using polymerase chain reaction (PCR) and Sanger sequencing. The CYP2A6*4 allele was identified by an allele-specific PCR assay. Bladder cancer risk was evaluated using the activity score (AS) system based on CYP2A6 genotypes. The odds ratios (95% confidence interval) for the AS 0, AS 0.5, AS 1.0, and AS 1.5 groups were 0.46 (0.12-1.83), 0.43 (0.15-1.25), 0.86 (0.40-1.86), and 1.36 (0.60-3.06), respectively. In conclusion, although decreased CYP2A6 AS tended to reduce the risk of bladder cancer in Japanese smokers, no significant association was recognized in this population. However, given the relatively small size of the sample, further study is required to conclude the lack of a statistically significant association between CYP2A6 genotypes and the risk of bladder cancer.
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Affiliation(s)
- Masaki Kumondai
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University
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Hosono H, Kumondai M, Arai T, Sugimura H, Sasaki T, Hirasawa N, Hiratsuka M. CYP2A6 genetic polymorphism is associated with decreased susceptibility to squamous cell lung cancer in Japanese smokers. Drug Metab Pharmacokinet 2015; 30:263-268. [PMID: 26091970 DOI: 10.1016/j.dmpk.2015.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 04/06/2015] [Accepted: 04/08/2015] [Indexed: 11/30/2022]
Abstract
Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of tobacco carcinogens, which are important risk factors in lung cancer. We and others have previously reported that CYP2A6*4, a whole-gene deletion polymorphism, is associated with lower risk of lung cancer than the wild-type allele. However, the genotyping method used in these previous studies considered only the CYP2A6*4 allele; this lead to insufficient classification of the CYP2A6 genotype, thereby underestimating the frequencies of the deficient alleles. In this study, CYP2A6 genotypes of Japanese smokers (110 individuals with squamous cell lung cancer (SQCC) and 132 sex-matched cancer-free controls) were determined using a sequencing-based approach to determine CYP2A6 haplotypes. The risk of SQCC was evaluated using the activity score (AS) system to predict CYP2A6 phenotype from its genotype. The risk of developing SQCC was significantly lower in the poor metabolizers assigned as AS 0.5 (adjusted odds ratio [OR] = 0.13, 95% CI = 0.04-0.45, P = 0.001) and AS 0 (adjusted OR = 0.15, 95% CI = 0.03-0.82, P = 0.028) than in the extensive metabolizers assigned as AS 2.0. In conclusion, CYP2A6 genetic polymorphisms may play important roles in the development of SQCC in Japanese smokers.
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Affiliation(s)
- Hiroki Hosono
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Masaki Kumondai
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takamitsu Sasaki
- Department of Environmental and Health Science, Tohoku Pharmaceutical University, Sendai, Japan
| | - Noriyasu Hirasawa
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Masahiro Hiratsuka
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
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15
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Pang C, Liu JH, Xu YS, Chen C, Dai PG. The allele frequency of CYP2A6*4 in four ethnic groups of China. Exp Mol Pathol 2015; 98:546-8. [PMID: 25862079 DOI: 10.1016/j.yexmp.2015.03.040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 03/22/2015] [Accepted: 03/27/2015] [Indexed: 11/24/2022]
Abstract
The CYP2A6*4 allele, characterized as the whole deletion of this gene, is closely associated with nicotine dependence, cancer susceptibility, and drug responsiveness. The frequency of this molecular variant differs across populations. Although genetic polymorphisms of CYP2A6*4 and its functional results have been reported in Chinese Han population, the allele frequency of CYP2A6*4 was largely unknown in other Chinese ethnic population. In this study, we investigated the allele frequency of CYP2A6*4 in four main ethnic groups of China based on our newly developed quantitative real-time PCR assay. The frequencies of the CYP2A6*4 allele were 7.9%, 15%, 0% and 2% in Han (N=120), Uighur (N=100), Bouyei (N=100) and Tibetan (N=100) (P<0.0001), respectively. This work greatly expanded our understanding of the distribution of CYP2A6*4 in Chinese population and provided more information of different ethnic population's smoking behavior and also in disease susceptibility and drug response.
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Affiliation(s)
- Cong Pang
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Jin-Hui Liu
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Yi-Song Xu
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Chao Chen
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China
| | - Peng-Gao Dai
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, PR China.
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Xie C, Wen X, Niu Z, Ding P, Liu T, He Y, Lin J, Yuan S, Guo X, Jia D, Chen W. Combinations ofCYP2A6*4and Glutathione S-Transferases Gene Polymorphisms Modify the Association Between Maternal Secondhand Smoke Exposure During Pregnancy and Small-for-Gestational-Age. Nicotine Tob Res 2015; 17:1421-7. [DOI: 10.1093/ntr/ntv072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 03/12/2015] [Indexed: 11/12/2022]
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Genotyping of wild-type cytochrome P450 2A6 and whole-gene deletion using human blood samples and a multiplex real-time polymerase chain reaction method with dual-labeled probes. Clin Chim Acta 2014; 441:71-4. [PMID: 25532948 DOI: 10.1016/j.cca.2014.12.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 12/06/2014] [Accepted: 12/15/2014] [Indexed: 01/30/2023]
Abstract
BACKGROUND Genetic polymorphisms of human cytochrome P450 2A6 (CYP2A6) are one of the determinants of smoking behavior and/or tobacco-related lung cancer risk in male Japanese smokers. To help identify those at high risk, we developed a multiplex real-time polymerase chain reaction (PCR)-based genotyping method with dual-labeled probes to detect wild-type and whole-gene deletion of CYP2A6 directly from blood samples without DNA isolation. METHODS We validated the new real-time PCR method that uses dual-labeled probes by utilizing 116 genomic DNA samples that had been genotyped previously and 33 blood samples. RESULTS The new method could discriminate CYP2A6 from highly homologous CYP2A7 and CYP2A13 genes and could also determine CYP2A6*1 (wild type) and CYP2A6*4 (whole-gene deletion) alleles in perfect accordance with previous analysis data. Amplification curve profiles were obtained by multiplex real-time PCR assay with CYP2A6*1 and CYP2A6*4 primer sets and dual-labeled probes using one-drop blood samples previously genotyped for CYP2A6*1/*1, CYP2A6*1/*4, and CYP2A6*4/*4. CONCLUSIONS A real-time multiplex PCR assay for genotyping wild-type CYP2A6 and whole-gene deletion was developed with dual-labeled probes. The new method achieved 100% agreement with data from the conventional PCR method for 116 genomic DNA samples and samples from 33 volunteers, thereby establishing its validity.
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Suter MA, Mastrobattista J, Sachs M, Aagaard K. Is there evidence for potential harm of electronic cigarette use in pregnancy? ACTA ACUST UNITED AC 2014; 103:186-95. [PMID: 25366492 DOI: 10.1002/bdra.23333] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Use of electronic cigarettes (e-cigarettes) and other nicotine containing products is increasing among women of reproductive age. The short- and long-term effects of these products on both mother and fetus are unknown. METHODS Because e-cigarettes are nicotine delivery systems, we sought to conduct a comprehensive review of the effects of nicotine on the fetus. RESULTS In utero nicotine exposure in animal models is associated with adverse effects for the offspring lung, cardiovascular system and brain. In the lung, this included reduced surface area, weight, and volume, as well as emphysema-like lesions. In adulthood, exposed offspring demonstrate elevated blood pressure and increased perivascular adipose tissue. In the brain, exposure alters offspring serotonergic, dopaminergic, and norepinephrine networks, which in turn are associated with behavioral and cognitive impairments. We also review current data on the lack of efficacy of nicotine replacement therapy in pregnant women, and highlight different nicotine containing products such as snuff, snus, and hookah. CONCLUSION We conclude that no amount of nicotine is known to be safe during pregnancy, and studies specifically addressing this risk are crucial and an imminent public health issue.
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Affiliation(s)
- Melissa A Suter
- Baylor College of Medicine, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Houston, Texas
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Aklillu E, Djordjevic N, Carrillo JA, Makonnen E, Bertilsson L, Ingelman-Sundberg M. High CYP2A6 enzyme activity as measured by a caffeine test and unique distribution of CYP2A6 variant alleles in Ethiopian population. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2013; 18:446-53. [PMID: 24380444 DOI: 10.1089/omi.2013.0140] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CYP2A6 metabolizes clinically relevant drugs, including antiretroviral and antimalarial drugs of major public health importance for the African populations. CYP2A6 genotype-phenotype relationship in African populations, and implications of geographic differences on enzyme activity, remain to be investigated. We evaluated the influence of CYP2A6 genotype, geographical differences, gender, and cigarette smoking on enzyme activity, using caffeine as a probe in 100 healthy unrelated Ethiopians living in Ethiopia, and 72 living in Sweden. CYP2A6 phenotype was estimated by urinary 1,7-dimethyluric acid (17U)/1,7-dimethylxanthine or paraxanthine (17X) ratio. The frequencies of CYP2A6*1B, *1D, *2, *4, *9, and *1x2 in Ethiopians were 31.3, 29.4, 0.6, 0.6, 2.8, and 0.3%, respectively. The overall mean±SD for log 17U/17X was 0.12±0.24 and coefficient of variation 199%. No significant difference in the mean log 17U/17X ratio between Ethiopians living in Sweden versus Ethiopia was observed. Analysis of variance revealed CYP2A6 genotype (p=0.04, F=2.01) but not geographical differences, sex, or cigarette smoking as predictors of CYP2A6 activity. Importantly, the median (interquartile range) of 17U/17X ratio in Ethiopians 1.35 (0.99 to 1.84) was 3- and 11-fold higher than the previously reported value in Swedes 0.52 (0.27 to 1.00) and Koreans 0.13 (0.0 to 0.35), respectively (Djordjevic et al., 2013). Taken together, we report here the relevance of CYP2A6 genotype for enzyme activity in this Ethiopian sample, as well as high CYP2A6 activity and unique distribution of the CYP2A6 variant alleles in Ethiopians as compared other populations described hitherto. Because Omics biomarker research is rapidly accelerating in Africa, CYP2A6 pharmacogenetics and clinical pharmacology observations reported herein for the Ethiopian populations have clinical and biological importance to plan for future rational therapeutics efforts in the African continent as well as therapeutics as a global science.
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Affiliation(s)
- Eleni Aklillu
- 1 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital , Karolinska Institutet, Stockholm, Sweden
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Cytochrome p450 metabolism of betel quid-derived compounds: implications for the development of prevention strategies for oral and pharyngeal cancers. ScientificWorldJournal 2013; 2013:618032. [PMID: 23983642 PMCID: PMC3747400 DOI: 10.1155/2013/618032] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 05/20/2013] [Indexed: 11/17/2022] Open
Abstract
Betel quid (BQ) products, with or without tobacco, have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx. There are estimated 600 million BQ users worldwide. In Taiwan alone there are 2 million habitual users (approximately 10% of the population). Oral and pharyngeal cancers result from interactions between genes and environmental factors (BQ exposure). Cytochrome p450 (CYP) families are implicated in the metabolic activation of BQ- and areca nut-specific nitrosamines. In this review, we summarize the current knowledge base regarding CYP genetic variants and related oral disorders. In clinical applications, we focus on cancers of the oral cavity and pharynx and OPMDs associated with CYP gene polymorphisms, including CYP1A1, CYP2A6, CYP2E1, and CYP26B1. Our discussion of CYP polymorphisms provides insight into the importance of screening tests in OPMDs patients for the prevention of oral and pharyngeal cancers. Future studies will establish a strong foundation for the development of chemoprevention strategies, polymorphism-based clinical diagnostic tools (e.g., specific single-nucleotide polymorphism (SNP) "barcodes"), and effective treatments for BQ-related oral disorders.
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Martiny VY, Miteva MA. Advances in molecular modeling of human cytochrome P450 polymorphism. J Mol Biol 2013; 425:3978-92. [PMID: 23856621 DOI: 10.1016/j.jmb.2013.07.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 07/01/2013] [Accepted: 07/02/2013] [Indexed: 01/08/2023]
Abstract
Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the drugs involved in ADR, 56% are metabolized by polymorphic phase I metabolizing enzymes, 86% among them being CYP. Here, we review the major CYP polymorphic forms, their impact for drug response and current advances in molecular modeling of CYP polymorphism. We focus on recent studies exploring CYP polymorphism performed by the use of sequence-based and/or protein-structure-based computational approaches. The importance of understanding the molecular mechanisms related to CYP polymorphism and drug response at the atomic level is outlined.
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Affiliation(s)
- Virginie Y Martiny
- Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, 35 rue Helene Brion, 75013 Paris, France; Inserm, U973, F-75205 Paris, France
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22
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Liu YL, Xu Y, Li F, Chen H, Guo SL. CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis. Tumour Biol 2013; 34:2651-7. [PMID: 23649654 DOI: 10.1007/s13277-013-0815-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 04/18/2013] [Indexed: 11/28/2022] Open
Abstract
Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of some tobacco carcinogens, which is an important risk factor of lung cancer. Among CYP2A6 allelic variants, CYP2A6*4 presents a whole gene deletion that accounts for the majority of poor metabolizer. In this study, a meta-analysis was performed to assess the association between CYP2A6*4 and risk of lung cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to December 20, 2012. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model and a random-effects model when appropriate. Eight eligible studies with 3,203 lung cancer cases and 2,839 controls were included in this study. Overall, no significant association was observed in CYP2A6*4 with the risk of lung cancer under any genetic model for all samples after correction. However, subgroup analysis showed that significant associations were observed in Asian with pooled OR (95 %CI) of 0.761 (0.672-0.861) for allele comparison, 0.769 (0.668-0.886) for dominant model, and 0.522 (0.359-0.760) for recessive model. Furthermore, after stratifying Asian samples according to smoking status, significant associations were only observed in smokers with pooled OR (95 %CI) of 0.713 (0.607-0.838) for allele comparison, 0.720 (0.596-0.869) for dominant model, and 0.444 (0.275-0.715) for recessive model. This meta-analysis suggests that the CYP2A6*4 polymorphism was associated with susceptibility of lung cancer for smokers in Asian. The whole gene deletion of CYP2A6 might decrease the risk of tobacco-related lung cancer in Asian.
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Affiliation(s)
- Yu-liang Liu
- Department of Respiratory Medicine, The first affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
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Wang L, Zang W, Liu J, Xie D, Ji W, Pan Y, Li Z, Shen J, Shi Y. Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis. PLoS One 2013; 8:e59556. [PMID: 23585826 DOI: 10.1371/journal.pone.0059556] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 02/15/2013] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVES To assess the association between the variant of Cytochrome P450 2A6 whole gene deletion (CYP2A6*4) polymorphism and risk of lung cancer. METHODS Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP2A6*4 and lung cancer were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS This meta-analysis included seven eligible studies, which included 2524 lung cancer cases and 2258 controls (cancer-free). Overall, CYP2A6*4 was associated with the risk of lung cancer (allele*4 vs. allele non-*4, pooled OR = 0.826, 95% CI = 0.725-0.941, P-value = 0.004). When stratifying for population, significant association was observed in Asian (additive model, pooled OR = 0.794, 95% CI = 0.694-0.909, P-value = 0.001; dominant model, pooled OR = 0.827, 95% CI = 0.709-0.965, P-value = 0.016; recessive model (pooled OR = 0.444, 95% CI = 0.293-0.675, P-value <0.0001). In the overall analysis, a comparably significant decrease in the frequency of *4/*4 genotype was detected between cases and controls in Asian while no *4/*4 genotype was detected in Caucasian in collected data. CONCLUSION This meta-analysis suggests that the CYP2A6*4 polymorphism is associated with susceptibility of lung cancer in Asian. The whole gene deletion of CYP2A6 may decrease the risk of lung cancer in Asian samples.
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Affiliation(s)
- Lishan Wang
- Bio-X Institutes and Affiliated Changning Mental Health Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, PR China
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PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. Pharmacogenet Genomics 2013; 22:695-708. [PMID: 22547082 DOI: 10.1097/fpc.0b013e3283540217] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Djordjevic N, Carrillo JA, van den Broek MP, Kishikawa J, Roh HK, Bertilsson L, Aklillu E. Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans. Drug Metab Pharmacokinet 2013; 28:93-7. [DOI: 10.2133/dmpk.dmpk-12-rg-029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Uno T, Obe Y, Ogura C, Goto T, Yamamoto K, Nakamura M, Kanamaru K, Yamagata H, Imaishi H. Metabolism of 7-ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants. Biopharm Drug Dispos 2012; 34:87-97. [DOI: 10.1002/bdd.1825] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 10/16/2012] [Accepted: 10/23/2012] [Indexed: 12/13/2022]
Affiliation(s)
- Tomohide Uno
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Yuichiro Obe
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Chika Ogura
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Tatsushi Goto
- Functional Analysis of Environmental Genes, Research Center for Environmental Genomics; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Kohei Yamamoto
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Masahiko Nakamura
- Department of Bioscience and Biotechnology, Faculty of Bioenvironmental Science; Kyoto Gakuen University; 1-1 Nanjo, Sogabe; Kameoka; Kyoto; 621-8555; Japan
| | - Kengo Kanamaru
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Hiroshi Yamagata
- Laboratory of Biological Chemistry, Department of Biofunctional Chemistry, Faculty of Agriculture; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
| | - Hiromasa Imaishi
- Functional Analysis of Environmental Genes, Research Center for Environmental Genomics; Kobe University; Nada-ku; Kobe; Hyogo; 657-8501; Japan
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Relationship between amounts of daily cigarette consumption and abdominal obesity moderated by CYP2A6 genotypes in Chinese male current smokers. Ann Behav Med 2012; 43:253-61. [PMID: 22160797 DOI: 10.1007/s12160-011-9318-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established. PURPOSE This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes. METHODS Nine hundred fifty-four male current smokers were selected. A venous specimen was collected to test serum cotinine and CYP2A6 genotype, and all smokers were divided into heavy (>15 cigarettes/day) and light smokers (≤15 cigarettes/day). RESULTS Heavy smoking increased the risk of abdominal obesity (odds ratio (OR) = 1.57; 95% CI, 1.13-2.19) compared with light smoking. Furthermore, heavy smoking had a positive interactive effect with CYP2A6 poor metabolizer genotype on abdominal obesity (OR = 3.90; 95% CI, 1.25-12.18). Moreover, CYP2A6 poor metabolizer genotypes were associated with slower nicotine metabolism. CONCLUSIONS Heavy smoking may increase the risk of abdominal obesity-particularly in smokers with CYP2A6 poor metabolizer genotypes.
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Han S, Choi S, Chun YJ, Yun CH, Lee CH, Shin HJ, Na HS, Chung MW, Kim D. Functional characterization of allelic variants of polymorphic human cytochrome P450 2A6 (CYP2A6*5, *7, *8, *18, *19, and *35). Biol Pharm Bull 2012; 35:394-9. [PMID: 22382327 DOI: 10.1248/bpb.35.394] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cytochrome P450 2A6 (CYP2A6) catalyzes important metabolic reactions of many xenobiotic compounds, including coumarin, nicotine, cotinine, and clinical drugs. Genetic polymorphisms of CYP2A6 can influence its metabolic activities. This study analyzed the functional activities of six CYP2A6 allelic variants (CYP2A6*5, *7, *8, *18, *19, and *35) containing nonsynonymous single-nucleotide polymorphisms. Recombinant variant enzymes of CYP2A6*7, *8, *18, *19, and *35 were successfully expressed in Escherichia coli and purified. However, a P450 holoenzyme spectrum was not detected for the CYP2A6*5 allelic variant (G479V). Structural analysis shows that the G479V mutation may alter the interaction between the A helix and the F-G helices. Enzyme kinetic analyses indicated that the effects of mutations in CYP2A6 allelic variants on drug metabolism are dependent on the substrates. In the case of coumarin 7-hydroxylation, CYP2A6*8 and *35 displayed increased K(m) values whereas CYP2A6*18 and *19 showed decreased k(cat) values, which resulted in lower catalytic efficiencies (k(cat)/K(m)). In the case of nicotine 5-oxidation, the CYP2A6*19 variant exhibited an increased K(m) value, whereas CYP2A6*18 and *35 showed much greater decreases in k(cat) values. These results suggest that individuals carrying these allelic variants are likely to have different metabolisms for different CYP2A6 substrates. Functional characterization of these allelic variants of CYP2A6 can help determine the importance of CYP2A6 polymorphisms in the metabolism of many clinical drugs.
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Affiliation(s)
- Songhee Han
- Department of Biological Sciences, Konkuk University, Seoul, Korea
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McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol 2012; 8:371-82. [PMID: 22288606 DOI: 10.1517/17425255.2012.657626] [Citation(s) in RCA: 199] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Variability of drug response is an important consideration in clinical medicine. A major determinant of drug response variability is hepatic cytochrome P450 oxidase (CYP450)-mediated drug metabolism. Advances in genetics permits genotyping large numbers of patients to identify single nucleotide polymorphisms (SNPs) which may result in variant CYP450 enzyme expression and/or activity. New SNPs with functional impacts are constantly being identified which further explain variability in CYP450 phenotype. AREAS COVERED The racial/ethnic distribution of selected CYP450 (CYP1A2, P2C8/9/19, 2D6 and 3A4/5) SNPs are reviewed with an emphasis on the agreement between genotype and phenotype. The reader will gain insight into the SNP distribution by racial/ethnic group and the corresponding relationship between important, highly prevalent, SNPs and their impact on metabolic phenotype. EXPERT OPINION Racial/ethnic differences in metabolic phenotype can be explained by differences in SNP distribution. However, overlap in substrate specificity, linkage disequilibrium and previously unidentified SNPs have made phenotypic characterization difficult for CYP3A4/5 and 2C8/9. Studies utilizing newly identified, highly prevalent, racially stratified SNPs and their impact on CYP isoform-specific metabolism will provide new answers.
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Affiliation(s)
- Joseph McGraw
- Concordia University Wisconsin, School of Pharmacy, 12800 N. Lakeshore Drive, Mequon, WI 53022, USA.
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Lee IS, Kim D. Polymorphic metabolism by functional alterations of human cytochrome P450 enzymes. Arch Pharm Res 2011; 34:1799-816. [PMID: 22139682 DOI: 10.1007/s12272-011-1103-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 08/24/2011] [Indexed: 10/14/2022]
Abstract
The study of cytochrome P450 pharmacogenomics is of particular interest because of its promise in the development of rational means to optimize drug therapy with respect to patient's genotype to ensure maximum efficacy with minimal adverse effects. Drug metabolizing P450 enzymes are polymorphic and are the main phase I enzymes responsible for the metabolism of clinical drugs. Therefore, polymorphisms in the P450s have the most impact on the fate of clinical drugs in phase I metabolism since almost 80% of drugs in use today are metabolized by these enzymes. Predictive genotyping for P450 enzymes for a more effective therapy will be routine for specific drugs in the future. In this review, we discuss the current knowledge of polymorphic metabolism by functional alterations in nonsynonymous SNPs of P450 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes.
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Affiliation(s)
- Im-Soon Lee
- Department of Biological Sciences and Center for Biotechnology Research in UBITA, Konkuk University, Seoul 143-701, Korea
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Yusof W, Hua GS. Gene, ethnic and gender influences predisposition of adverse drug reactions to artesunate among Malaysians. Toxicol Mech Methods 2011; 22:184-92. [PMID: 22003869 DOI: 10.3109/15376516.2011.623331] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
CONTEXT Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. OBJECTIVE In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population. MATERIALS AND METHODS In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n = 24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants. RESULTS The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs. DISCUSSION Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p < 0.05). CONCLUSION It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.
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Affiliation(s)
- Wardah Yusof
- Department of Pharmacology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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Liu T, David SP, Tyndale RF, Wang H, Zhou Q, Ding P, He YH, Yu XQ, Chen W, Crump C, Wen XZ, Chen WQ. Associations of CYP2A6 genotype with smoking behaviors in southern China. Addiction 2011; 106:985-94. [PMID: 21205058 PMCID: PMC3074015 DOI: 10.1111/j.1360-0443.2010.03353.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers. DESIGN Case-only genetic association study. SETTING Southern China. PARTICIPANTS A total of 1328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007. MEASUREMENTS All participants answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles were genotyped for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6*4,*5,*7,*9 and *10). FINDINGS The frequencies of CYP2A6*4, *5, *7, *9 and *10 alleles were 8.5, 1.2, 6.3, 13.5 and 2.4%, which corresponded to 48.9, 15.4, 24.2 and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses in male smokers demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day [adjusted odds ratio (OR) = 0.49; 95% confidence interval (CI): 0.32-0.76], started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06-2.26) and, among former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12-0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (adjusted OR = 0.54; 95% CI: 0.34-0.86). CONCLUSIONS Reduced metabolism function of cytochrome P450 2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.
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Affiliation(s)
- Tao Liu
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, 74, Zhongshan Road 2, 510080, Guangzhou, China
| | - Sean P. David
- Center for Education in Family & Community Medicine and the Division of Family & Community Medicine, Stanford University, 1215 Welch Road, Modular G, Stanford, CA 94305, USA
- SRI International, 333 Ravenswood Ave, Menlo Park, CA 943025, USA
- Center for Primary Care & Prevention and the Department of Family Medicine, Brown Alpert Medical School, 111 Brewster Street, Pawtucket, RI 02860
| | - Rachel F. Tyndale
- The Center for Addiction and Mental Health and the Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Canada M5S 1A8
| | - Hui Wang
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, 74, Zhongshan Road 2, 510080, Guangzhou, China
| | - Qian Zhou
- The Center for Addiction and Mental Health and the Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Canada M5S 1A8
| | - Peng Ding
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, 74, Zhongshan Road 2, 510080, Guangzhou, China
| | - Yan-Hui He
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, 74, Zhongshan Road 2, 510080, Guangzhou, China
| | - Xue-Qing Yu
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-Sen University, 58, Zhongshan Road 2, 510080, Guangzhou, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-Sen University, 58, Zhongshan Road 2, 510080, Guangzhou, China
| | - Casey Crump
- Center for Education in Family & Community Medicine and the Division of Family & Community Medicine, Stanford University, 1215 Welch Road, Modular G, Stanford, CA 94305, USA
| | - Xiao-Zhong Wen
- Department of Community Health, Brown University, Providence, RI, USA
| | - Wei-Qing Chen
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, 74, Zhongshan Road 2, 510080, Guangzhou, China
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Soriano A, Vicente J, Carcas C, Gonzalez-Andrade F, Arenaz I, Martinez-Jarreta B, Fanlo A, Mayayo E, Sinués B. Differences between Spaniards and Ecuadorians in CYP2A6 allele frequencies: comparison with other populations. Fundam Clin Pharmacol 2011; 25:627-32. [DOI: 10.1111/j.1472-8206.2010.00889.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
The development of substance dependence requires the initiation of substance use and the conversion from experimental use to established use before development of dependence. Numerous large twin studies have indicated a significant genetic contribution to this process. Genetic studies to date have been most successful at identifying genetic factors that influence the transition from regular use to dependence. The availability of large cohort samples for nicotine and alcohol dependence has resulted in significant progress being made in understanding at least some of the genetic contributions to these addictions. Fewer studies have replicated specific genetic contributions to illicit drug use, though it is clear that there is a strong genetic component involved here as well. Substance dependence can be thought of as a pharmacogenetic illness, and most likely hundreds and more probably thousands of genetic variants will be required to fully explain the genetic input to this disease.
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Affiliation(s)
- Laura Jean Bierut
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Krishnakumar D, Gurusamy U, Dhandapani K, Surendiran A, Baghel R, Kukreti R, Gangadhar R, Prayaga U, Manjunath S, Adithan C. Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Fundam Clin Pharmacol 2011; 26:295-306. [PMID: 21265876 DOI: 10.1111/j.1472-8206.2010.00917.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population.
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Affiliation(s)
- D Krishnakumar
- ICMR Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry 605 006, India
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Aagaard-Tillery K, Spong CY, Thom E, Sibai B, Wendel G, Wenstrom K, Samuels P, Simhan H, Sorokin Y, Miodovnik M, Meis P, O'Sullivan MJ, Conway D, Wapner RJ, Eunice Kennedy Shriver National Institute of Child Health, Human Development (NICHD) Maternal–Fetal Medicine Units Network (MFMU). Pharmacogenomics of maternal tobacco use: metabolic gene polymorphisms and risk of adverse pregnancy outcomes. Obstet Gynecol 2010; 115:568-577. [PMID: 20177288 PMCID: PMC3263385 DOI: 10.1097/aog.0b013e3181d06faf] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To assess whether functional maternal or fetal genotypes along well-characterized metabolic pathways (ie, CYP1A1, GSTT1, and CYP2A6) may account for varying associations with adverse outcomes among pregnant women who smoke. METHODS DNA samples from 502 smokers and their conceptuses, alongside women in a control group, were genotyped for known functional allelic variants of CYP1A1 (Ile462Val AA>AG/GG), GSTT1(del), and CYP2A6 (Lys160His T>A). Modification of the association between smoking and outcome by genotype was evaluated. Outcomes included birth weight, pregnancy loss, preterm birth, small for gestational age, and a composite outcome composed of the latter four components plus abruption. RESULTS No interaction between maternal or fetal genotype of any of the polymorphisms and smoking could be demonstrated. In contrast, the association of smoking with gestational age-adjusted birth weight (birth weight ratio) was modified by fetal GSTT1 genotype (P for interaction=.02). Fetuses with GSTT1(del) had a mean birth weight reduction among smokers of 262 g (P=.01), whereas in fetuses without the GSTT1(del) the effect of tobacco exposure was nonsignificant (mean reduction 87 g, P=.16). After adjusting for confounding, results were similar. CONCLUSION Fetal GSTT1 deletion significantly and specifically modifies the effect of smoking on gestational age-corrected birth weight.
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Affiliation(s)
- Kjersti Aagaard-Tillery
- From the Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah; University of Tennessee, Memphis, Tennessee; University of Texas Southwestern Medical Center, Dallas, Texas; University of Alabama at Birmingham, Birmingham, Alabama; The Ohio State University, Columbus, Ohio; University of Pittsburgh, Pennsylvania; Wayne State University, Detroit, Michigan; University of Cincinnati, Cincinnati, Ohio; Wake Forest University Health Services, Winston-Salem, North Carolina; University of Miami, Miami, Florida; University of Texas at San Antonio, San Antonio, Texas; Thomas Jefferson University, Philadelphia, Pennsylvania; The George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy Shriver National Institute for Child Health and Human Development, Bethesda, Maryland
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In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population. Eur J Clin Pharmacol 2010; 66:571-8. [PMID: 20155256 DOI: 10.1007/s00228-010-0785-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Accepted: 01/11/2010] [Indexed: 10/19/2022]
Abstract
PURPOSE The main aim of the study was to investigate the distribution of cytochrome P450 2A6 (CYP2A6) and xanthine oxidase (XO) enzyme activities in the Serbian population. Secondly, we tested the influence of genetics (CYP2A6 polymorphism), sex, and cigarette smoking on both enzymes. METHODS One hundred forty healthy Serbian volunteers were genotyped for common CYP2A6 alleles. In 100 of them, CYP2A6 and XO activities were determined by the urinary 17U/17X and 1U/(1U + 1X) ratios, respectively, after oral administration of 100 mg caffeine as a probe. RESULTS A 21-fold variation in the 17U/17X ratio was observed (range: 0.49-10.28, mean = 1.65, 95% CI: 1.49-1.83). The urinary 1U/(1U + 1X) ratios displayed four-fold variation, ranging from 0.17 to 0.71 (mean = 0.43, 95% CI: 0.41-0.45). CYP2A6 alleles *1A, *1B1, *9, *4 and *1B1x2 were found with frequencies of 0.579, 0.307, 0.082, 0.029, and 0.004 respectively. CYP2A6*5 was not detected. CYP2A6 genotype influenced interindividual variability in CYP2A6 enzyme activity (P = 0.04). Cigarette smoking inhibited CYP2A6 enzyme activity (P = 0.02), but had no effect on activity of XO (P = 0.16).There was no significant difference between men and women in terms of CYP2A6 or XO activity. CONCLUSIONS Serbs displayed interindividual variations in CYP2A6 activity. CYP2A6 genotype and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity. Unimodal distribution of XO enzyme activity in Serbs implies the absence of subjects with low enzyme activity in this population. XO activity is not influenced by sex or cigarette smoking.
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 541] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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Abstract
Studies of environmental challenges, such as hazardous air pollutants, nonmutagenic toxins, diet choice, and maternal behavioral patterns, reveal changes in gene expression patterns, DNA methylation, and histone modifications that are in causal association with exogenous exposures. In this article we summarize some of the recent advances in the field of environmental epigenetics and highlight seminal studies that implicate in utero exposures as causative agents in altering not only the epigenome of the exposed gestation, but that of subsequent generations. Current studies of the effects of maternal behavior, exposure to environmental toxins, and exposure to maternal diet and an altered gestational milieu are summarized.
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Affiliation(s)
- Melissa A Suter
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
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40
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Gene–gene interactions of CYP2A6 and MAOA polymorphisms on smoking behavior in Chinese male population. Pharmacogenet Genomics 2009; 19:345-52. [DOI: 10.1097/fpc.0b013e328329893c] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Yusof W, Gan SH. High prevalence of CYP2A6⁎4 and CYP2A6⁎9 alleles detected among a Malaysian population. Clin Chim Acta 2009; 403:105-9. [DOI: 10.1016/j.cca.2009.01.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 01/28/2009] [Accepted: 01/28/2009] [Indexed: 10/21/2022]
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Wang LL, Li Y, Zhou SF. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Drug Metab Dispos 2009; 37:977-91. [PMID: 19204079 DOI: 10.1124/dmd.108.026047] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease and altered drug response. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment, and conducting individualized pharmacotherapy. Numerous nsSNPs have been found in genes coding for human cytochromes P450 (P450s), but there is poor knowledge on the relationship between the genotype and phenotype of nsSNPs in P450s. We have identified 791 validated nsSNPs in 57 validated human CYP genes from the National Center for Biotechnology Information Database of Single Nucleotide Polymorphism and Swiss-Prot database. Using the polymorphism phenotyping (PolyPhen; http://genetics.bwh.harvard.edu/pph) and sorting intolerant from tolerant (SIFT; http://blocks.fhcrc.org/sift/SIFT.html) algorithms, 39 to 43% of nsSNPs in CYP genes were predicted to have functional impacts on protein function. There was a significant concordance between the predicted results using the SIFT and PolyPhen algorithms. A prediction accuracy analysis found that approximately 70% of nsSNPs were predicted correctly as damaging. Of nsSNPs predicted as deleterious, the prediction scores by the SIFT and PolyPhen algorithms were significantly associated with the numbers of nsSNPs with known phenotype confirmed by benchmarking studies, including site-directed mutagenesis analysis and clinical association studies. These amino acid substitutions are supposed to be the pathogenetic basis for the alteration of P450 enzyme activity and the association with disease susceptivity. This prediction analysis of nsSNPs in human CYP genes would be useful for further genotype-phenotype studies on individual differences in drug clearance and clinical response.
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Affiliation(s)
- Lin-Lin Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China
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Abstract
The molecular genetics of nicotine metabolism involves multiple polymorphic catalytic enzymes. Variation in metabolic pathways results in nicotine disposition kinetics that differ between individuals and ethnic groups. Twin studies indicate that a large part of this variance is genetic in origin, although environmental influences also contribute. The primary aim of this chapter is to review the current knowledge regarding the genetic variability in the enzymes that metabolize nicotine in humans. The focus is on describing the genetic polymorphisms that exist in cytochromes P450 (CYPs), aldehyde oxidase 1 (AOX1), UDP-glucuronosyltransferases (UGTs), and flavin-containing monooxygenase 3 (FMO3). Genetic studies have demonstrated that polymorphisms in CYP2A6, the primary enzyme responsible for nicotine breakdown, make a sizable contribution to the wide range of nicotine metabolic capacity observed in humans. Thus, special attention will be given to CYP2A6, because slower nicotine metabolism requires less frequent self-administration, and accordingly influences smoking behaviors. In addition, the molecular genetics of nicotine metabolism in nonhuman primates, mice, and rats will be reviewed briefly.
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Affiliation(s)
- Jill C Mwenifumbo
- Centre for Addiction & Mental Health and Department of Pharmacology, University of Toronto, Toronto, ON, Canada
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In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics 2009; 19:300-9. [DOI: 10.1097/fpc.0b013e328328d577] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Rossini A, de Almeida Simão T, Albano RM, Pinto LFR. CYP2A6 polymorphisms and risk for tobacco-related cancers. Pharmacogenomics 2008; 9:1737-52. [PMID: 19018727 DOI: 10.2217/14622416.9.11.1737] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Tobacco consumption is the main identifiable risk to cancer, contributing to the majority of tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco addiction, nicotine and the potent carcinogens present at high concentrations either in cigarette mainstream smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for enzymes with altered expression or metabolic capacity produce alterations in nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent carcinogen-metabolizing CYP enzymes may help to determine individuals that are at higher risk of developing tumors associated with tobacco consumption.
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Affiliation(s)
- Ana Rossini
- Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Departamento de Bioquímica Brazil, Rio de Janeiro, Brazil
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Abstract
Of the 57 human cytochromes P450 (P450) and 58 pseudogenes discovered to date, (http://drnelson.utmem.edu/CytochromeP450.html ), 1/4 still remain "orphans" in the sense that their function, expression sites, and regulation are still largely not elucidated. The post-human genome-sequencing project era has presented the research community with novel challenges. Despite many insights gathered about gene location and genetic variations in our human genome, we still lack important knowledge about these novel P450 enzymes and their functions in endogenous and exogenous metabolism, as well as their possible roles in the metabolism of toxicants and carcinogens. Our own list of such orphans currently consists of 13 members: P450 2A7, 2S1, 2U1, 2W1, 3A43, 4A22, 4F11, 4F22, 4V2, 4X1, 4Z1, 20A1, and 27C1. Some of the orphans, e.g. P450s 2W1 and 2U1, already have putative assigned functions in arachidonic acid metabolism and may activate carcinogens. However, at this point, for the majority of them more knowledge is available about their genes and single nucleotide polymorphisms than of their biological functions. It is noteworthy that most P450 orphans express high interspecies sequence conservation and have orthologs in rodents (e.g. CYP4X1/Cyp4x1, CYP4V2/Cyp4v3). This review summarizes recent knowledge about the P450 orphans and questions remaining about their specific roles in human metabolism.
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Affiliation(s)
- Katarina Stark
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA
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Nurfadhlina M, Foong K, Teh LK, Tan SC, Mohd Zaki S, Ismail R. CYP2A6 polymorphisms in Malays, Chinese and Indians. Xenobiotica 2008; 36:684-92. [PMID: 16891249 DOI: 10.1080/00498250600715932] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.
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Affiliation(s)
- M Nurfadhlina
- Pharmacogenetics Research Group, INFORMM, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine. Pharmacogenet Genomics 2008; 18:761-72. [DOI: 10.1097/fpc.0b013e328303c034] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Lee AS, Gutiérrez-Arcelus M, Perry GH, Vallender EJ, Johnson WE, Miller GM, Korbel JO, Lee C. Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies. Hum Mol Genet 2008; 17:1127-36. [PMID: 18180252 DOI: 10.1093/hmg/ddn002] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Copy number variants (CNVs) are heritable gains and losses of genomic DNA in normal individuals. While copy number variation is widely studied in humans, our knowledge of CNVs in other mammalian species is more limited. We have designed a custom array-based comparative genomic hybridization (aCGH) platform with 385 000 oligonucleotide probes based on the reference genome sequence of the rhesus macaque (Macaca mulatta), the most widely studied non-human primate in biomedical research. We used this platform to identify 123 CNVs among 10 unrelated macaque individuals, with 24% of the CNVs observed in multiple individuals. We found that segmental duplications were significantly enriched at macaque CNV loci. We also observed significant overlap between rhesus macaque and human CNVs, suggesting that certain genomic regions are prone to recurrent CNV formation and instability, even across a total of approximately 50 million years of primate evolution ( approximately 25 million years in each lineage). Furthermore, for eight of the CNVs that were observed in both humans and macaques, previous human studies have reported a relationship between copy number and gene expression or disease susceptibility. Therefore, the rhesus macaque offers an intriguing, non-human primate outbred model organism with which hypotheses concerning the specific functions of phenotypically relevant human CNVs can be tested.
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Affiliation(s)
- Arthur S Lee
- Department of Pathology, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115, USA
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Mwenifumbo JC, Lessov-Schlaggar CN, Zhou Q, Krasnow RE, Swan GE, Benowitz NL, Tyndale RF. Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism. Clin Pharmacol Ther 2008; 83:115-21. [PMID: 17522595 PMCID: PMC2921956 DOI: 10.1038/sj.clpt.6100246] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cytochrome P450 2A6 (CYP2A6) is the human enzyme responsible for the majority of nicotine's metabolism. CYP2A6 genetic variants contribute to the interindividual and interethnic variation in nicotine metabolism. We examined the association between the CYP2A6*1B variant and nicotine's in vivo metabolism. Intravenous infusions of deuterium-labeled nicotine were administered to 292 volunteers, 163 of whom were White and did not have common CYP2A6 variants, other than CYP2A6*1B. We discovered three novel CYP2A6*1B variants in the 3'-flanking region of the gene that can confound genotyping assays. We found significant differences between CYP2A6*1A/*1A, CYP2A6*1A/*1B, and CYP2A6*1B/*1B groups in total nicotine clearance (17.2+/-5.2, 19.0+/-6.4, and 20.4+/-5.9, P<0.02), non-renal nicotine clearance (16.4+/-5.0, 18.5+/-6.2, and 19.8+/-5.7, P<0.01), and the plasma trans-3'-hydroxycotinine/cotinine ratio (0.26+/-0.1, 0.26+/-0.1, and 0.34+/-0.1, P<0.001). There were also differences in total nicotine (29.4+/-12.9, 25.8+/-0.12.9, and 22.4+/-12.4, P<0.01), cotinine (29.2+/-8.1, 32.2+/-9.1, and 33.0+/-6.6, P<0.01) and trans-3'-hydroxycotinine (32.4+/-9.1, 34.2+/-12.3, and 41.3+/-11.3, P<0.001) excreted in the urine. We report evidence that CYP2A6*1B genotype is associated with faster nicotine clearance in vivo, which will be important to future CYP2A6 genotype association studies.
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Affiliation(s)
- Jill C. Mwenifumbo
- Centre for Addiction & Mental Health and Department of Pharmacology, University of Toronto, Toronto, Canada
| | | | - Qian Zhou
- Centre for Addiction & Mental Health and Department of Pharmacology, University of Toronto, Toronto, Canada
| | - Ruth E. Krasnow
- Center for Health Sciences, SRI International, Menlo Park, CA
| | - Gary E. Swan
- Center for Health Sciences, SRI International, Menlo Park, CA
| | - Neal L. Benowitz
- Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center and Departments of Medicine, Psychiatry and Biopharmaceutical Sciences, University of California San Francisco
| | - Rachel F. Tyndale
- Centre for Addiction & Mental Health and Department of Pharmacology, University of Toronto, Toronto, Canada
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