|
1
|
Chen Y, Johnson RE, Manderville RA, Liu J. A High-Affinity and Selective DNA Aptamer for the N-Linked C8-Deoxyguanosine Adduct Produced by the Arylamine Carcinogen 4-Aminobiphenyl. Chem Res Toxicol 2025; 38:340-346. [PMID: 39910765 DOI: 10.1021/acs.chemrestox.4c00496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
4-Aminobiphenyl (4-ABP) is a known human carcinogen that is implicated in the development of bladder cancers in smokers. The amine substituent undergoes bioactivation to generate nitrenium ions capable of covalently modifying DNA nucleobases. The primary adduct of 4-ABP, N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP), is a bulky N-linked C8-dG adduct that serves as a biomarker for assessing the cancer risk associated with aromatic amine exposure. In this study, the capture-SELEX method was utilized to isolate DNA aptamers for dG-C8-ABP with high affinity and specificity. Using thioflavin T fluorescence spectroscopy and isothermal titration calorimetry, the parent aptamer PdG-1 has a Kd value below 100 nM and over 50-fold selectivity for dG-C8-ABP against competing analytes. A turn-on fluorescent sensor for dG-C8-ABP diagnostics, developed using a strand displacement assay, is also presented with a limit of detection of 68 nM. Our work represents the first selection of a DNA aptamer for a bulky DNA adduct produced by a known human carcinogen and sets the stage for the creation of ultrasensitive aptasensor platforms to meet the challenge of dG-C8-ABP detection in clinical settings.
Collapse
Affiliation(s)
- Yijing Chen
- Department of Chemistry, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
| | - Ryan E Johnson
- Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Richard A Manderville
- Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Juewen Liu
- Department of Chemistry, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
| |
Collapse
|
|
2
|
Samuels ER, Sevrioukova IF. Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4. Chem Biol Drug Des 2025; 105:e70043. [PMID: 39792691 PMCID: PMC11749023 DOI: 10.1111/cbdd.70043] [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: 10/01/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 01/12/2025]
Abstract
A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R2 side-group and R3 end-group interplay when the R1 side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R1/R2-phenyl inhibitors upon elongation and/or fluorination of R3-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R3 is pyridine, the impact of R2-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R2-naphthalene/R3-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (Ks = 0.009 μM; IC50 = 0.10 μM). Introduction of a larger biphenyl or fluorene as R2 did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (Ks = 0.734 μM; IC50 = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R2-biphenyl, however, can switch positions with R3-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R2/R3 interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.
Collapse
Affiliation(s)
- Eric R. Samuels
- Department of Pharmaceutical Sciences, University of California, Irvine, California 92697-3900
| | - Irina F. Sevrioukova
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900
| |
Collapse
|
|
3
|
Devraj K, Kulkarni O, Liebner S. Regulation of the blood-brain barrier function by peripheral cues in health and disease. Metab Brain Dis 2024; 40:61. [PMID: 39671124 PMCID: PMC11645320 DOI: 10.1007/s11011-024-01468-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 09/12/2024] [Indexed: 12/14/2024]
Abstract
The blood-brain barrier (BBB) is formed by microvascular endothelial cells which are ensembled with pericytes, astrocytes, microglia and neurons in the neurovascular unit (NVU) that is crucial for neuronal function. Given that the NVU and the BBB are highly dynamic and regulated structures, their integrity is continuously challenged by intrinsic and extrinsic factors. Herein, factors from peripheral organs such as gonadal and adrenal hormones may influence vascular function also in CNS endothelial cells in a sex- and age-dependent manner. The communication between the periphery and the CNS likely takes place in specific areas of the brain among which the circumventricular organs have a central position due to their neurosensory or neurosecretory function, owing to physiologically leaky blood vessels. In acute and chronic pathological conditions like liver, kidney, pulmonary disease, toxins and metabolites are generated that reach the brain via the circulation and may directly or indirectly affect BBB functionality via the activation of the immunes system. For example, chronic kidney disease (CKD) currently affects more than 840 million people worldwide and is likely to increase along with western world comorbidities of the cardio-vascular system in continuously ageing societies. Toxins leading to the uremic syndrome, may further lead to neurological complications such as cognitive impairment and uremic encephalopathy. Here we summarize the effects of hormones, toxins and inflammatory reactions on the brain vasculature, highlighting the urgent demand for mechanistically exploring the communication between the periphery and the CNS, focusing on the BBB as a last line of defense for brain protection.
Collapse
Affiliation(s)
- Kavi Devraj
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, Telangana, India.
| | - Onkar Kulkarni
- Metabolic Disorders and Neuroscience Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, Telangana, India
| | - Stefan Liebner
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Partner Site Frankfurt, Frankfurt am Main, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.
| |
Collapse
|
|
4
|
Korucu EN, Aydemir S, Menevse E, Erkoc Kaya D, Azzawri AA. Gene expression of MTATP6 and cytochrome P450 in MCF-7 and MDA-MB -231 breast cancer cell lines with juglone and curcumin supplemented. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-17. [PMID: 39437263 DOI: 10.1080/15257770.2024.2418907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024]
Abstract
It is aimed to determine the effects of naphthoquinones as juglone and curcumin application on cell viability and expression analyzes of CYP3A4 and MTATP6 genes in MCF-7 and MDA-MB-231 human breast cancer cell lines. MCF-7 and MDA-MB-231 cells were incubated, were replaced with containing various concentrations of 5, 10, 15 μM curcumin and 5, 10, 15 μM juglone for MCF-7 and 1, 5, 10 μM curcumin and 1, 2, 3 μM juglone for MDA-MB-231 for 24 h. CYP3A4 and MTATP6 gene expression levels in both cell lines were determined by quantitative real-time polymerase chain reaction (qPCR) method and western blot method. IC50 values for 24 h were found as 22.41 μM for curcumin, and 16.27 μM for juglone in MCF-7, and 10.43 μM for curcumin, and 3.42 μM for juglone in MDA-MB-231 cells. Curcumin showed anti-proliferative, and antioxidant effects. CYP3A4 and MTATP6 gene expressions were decreased in MCF-7 breast cancer cell line when the cells treated with juglone or curcumin. CYP3A4 and MTATP6 gene expressions were decreased at all application doses of juglone in MDA-MB-231 cells whereas CYP3A4 and MTATP6 protein levels were only decreased at 10 μM curcumin compared with the control group.
Collapse
Affiliation(s)
- Emine Nedime Korucu
- Department of Molecular Biology and Genetics, Faculty of Science, Necmettin Erbakan University, Konya, Turkey
| | - Saliha Aydemir
- Department of Molecular Biology and Genetics, Faculty of Science, Necmettin Erbakan University, Konya, Turkey
| | - Esma Menevse
- Department of Medical Biochemistry, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Dudu Erkoc Kaya
- Department of Medical Biology, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Ali Ahmed Azzawri
- Department of Medical Genetics, Faculty of Medicine, Selcuk University, Konya, Turkey
| |
Collapse
|
|
5
|
Jacob SM, Lee S, Kim SH, Sharkey KA, Pfeffer G, Nguyen MD. Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis. Nat Rev Neurol 2024; 20:475-494. [PMID: 38965379 DOI: 10.1038/s41582-024-00991-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 07/06/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.
Collapse
Affiliation(s)
- Sarah M Jacob
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sukyoung Lee
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Seung Hyun Kim
- Department of Neurology, Hanyang University Hospital, Seoul, South Korea
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gerald Pfeffer
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - Minh Dang Nguyen
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| |
Collapse
|
|
6
|
El-Mahrouk SR, El-Ghiaty MA, Alqahtani MA, El-Kadi AOS. Dimethylmonothioarsinic acid (DMMTA V) differentially modulates the expression of AHR-regulated cytochrome P450 1A enzymes in vivo and in vitro. Toxicol Lett 2024; 394:32-45. [PMID: 38403205 DOI: 10.1016/j.toxlet.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/07/2024] [Accepted: 02/21/2024] [Indexed: 02/27/2024]
Abstract
Dimethylmonothioarsinic acid (DMMTAV), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTAV is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTAV's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice were intraperitoneally injected with 6 mg/kg DMMTAV, alone or with 15 μg/kg TCDD, for 6 and 24 h. Similarly, Hepa-1c1c7 cells were exposed to DMMTAV (0.5, 1, and 2 μM) with or without 1 nM TCDD for 6 and 24 h. DMMTAV hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6 h) and in vitro, associated with reduced CYP1A regulatory element activation. Interestingly, in C57BL/6 mice, DMMTAV boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTAV co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTAV negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTAV-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTAV differentially modulates the TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic.
Collapse
Affiliation(s)
- Sara R El-Mahrouk
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt
| | - Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
| |
Collapse
|
|
7
|
Frikha I, Frikha R, Medhaffer M, Charfi H, Turki F, Elloumi M. Impact of CYP1A1 variants on the risk of acute lymphoblastic leukemia: evidence from an updated meta-analysis. Blood Res 2024; 59:9. [PMID: 38485870 PMCID: PMC10917727 DOI: 10.1007/s44313-024-00007-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/24/2024] [Indexed: 03/18/2024] Open
Abstract
OBJECTIVE Our study aimed to investigate the association between cytochrome P450 1A1 (CYP1A1) polymorphisms (T3801C and A2455G) and acute lymphoblastic leukemia (ALL) risk, considering genetic models and ethnicity. MATERIALS AND METHODS PubMed, Embase, Web of Knowledge, Scopus, and the Cochrane electronic databases were searched using combinations of keywords related to CYP1A1 polymorphisms and the risk of ALL. Studies retrieved from the database searches underwent screening based on strict inclusion and exclusion criteria. RESULTS In total, 2822 cases and 4252 controls, as well as 1636 cases and 2674 controls of the C3801T and A2455G variants of CYP1A1, respectively, were included in this meta-analysis. The T3801C polymorphism of CYP1A1 significantly increases the risk of ALL, particularly those observed in Asian and Hispanic populations, independent of age. Similarly, the A2455G polymorphism of CYP1A1 plays a significant role in the susceptibility to ALL in all genetic models, except the heterozygous form. This association was observed mainly in mixed populations and in both children and adults (except in the heterozygous model). CONCLUSION Our comprehensive analysis indicates that the T3801 and A2455G polymorphisms of CYP1A1 may increase the risk of ALL depending on ethnicity. Therefore, both variants should be considered promising biomarkers for ALL risk. Further large-scale investigations are necessary to assess other factors, such as gene-gene or gene-environment interactions.
Collapse
Affiliation(s)
- Imen Frikha
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Rim Frikha
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia.
- Department of Medical Genetics, Hedi Chaker Hospital, Sfax, Tunisia.
| | - Moez Medhaffer
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Hanen Charfi
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| | - Fatma Turki
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Medical Genetics, Hedi Chaker Hospital, Sfax, Tunisia
| | - Moez Elloumi
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
- Department of Hematology, Hedi Chaker Hospital, Sfax, Tunisia
| |
Collapse
|
|
8
|
Ragi N, Walmsley SJ, Jacobs FC, Rosenquist TA, Sidorenko VS, Yao L, Maertens LA, Weight CJ, Balbo S, Villalta PW, Turesky RJ. Screening DNA Damage in the Rat Kidney and Liver by Untargeted DNA Adductomics. Chem Res Toxicol 2024; 37:340-360. [PMID: 38194517 PMCID: PMC10922321 DOI: 10.1021/acs.chemrestox.3c00333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Air pollution, tobacco smoke, and red meat are associated with renal cell cancer (RCC) risk in the United States and Western Europe; however, the chemicals that form DNA adducts and initiate RCC are mainly unknown. Aristolochia herbaceous plants are used for medicinal purposes in Asia and worldwide. They are a significant risk factor for upper tract urothelial carcinoma (UTUC) and RCC to a lesser extent. The aristolochic acid (AA) 8-methoxy-6-nitrophenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-I), a component of Aristolochia herbs, contributes to UTUC in Asian cohorts and in Croatia, where AA-I exposure occurs from ingesting contaminated wheat flour. The DNA adduct of AA-I, 7-(2'-deoxyadenosin-N6-yl)-aristolactam I, is often detected in patients with UTUC, and its characteristic A:T-to-T:A mutational signature occurs in oncogenes and tumor suppressor genes in AA-associated UTUC. Identifying DNA adducts in the renal parenchyma and pelvis caused by other chemicals is crucial to gaining insights into unknown RCC and UTUC etiologies. We employed untargeted screening with wide-selected ion monitoring tandem mass spectrometry (wide-SIM/MS2) with nanoflow liquid chromatography/Orbitrap mass spectrometry to detect DNA adducts formed in rat kidneys and liver from a mixture of 13 environmental, tobacco, and dietary carcinogens that may contribute to RCC. Twenty DNA adducts were detected. DNA adducts of 3-nitrobenzanthrone (3-NBA), an atmospheric pollutant, and AA-I were the most abundant. The nitrophenanthrene moieties of 3-NBA and AA-I undergo reduction to their N-hydroxy intermediates to form 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) adducts. We also discovered a 2'-deoxycytidine AA-I adduct and dA and dG adducts of 10-methoxy-6-nitro-phenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-III), an AA-I isomer and minor component of the herbal extract assayed, signifying AA-III is a potent kidney DNA-damaging agent. The roles of AA-III, other nitrophenanthrenes, and nitroarenes in renal DNA damage and human RCC warrant further study. Wide-SIM/MS2 is a powerful scanning technology in DNA adduct discovery and cancer etiology characterization.
Collapse
Affiliation(s)
| | | | | | - Thomas A Rosenquist
- Department of Pharmacological Science, Stony Brook University, Stony Brook, New York 11794, United States
| | - Viktoriya S Sidorenko
- Department of Pharmacological Science, Stony Brook University, Stony Brook, New York 11794, United States
| | | | | | | | | | | | | |
Collapse
|
|
9
|
Wang R, Liu Z, Gong J, Zhou Q, Guan X, Ge G. An Uncertainty-Guided Deep Learning Method Facilitates Rapid Screening of CYP3A4 Inhibitors. J Chem Inf Model 2023; 63:7699-7710. [PMID: 38055780 DOI: 10.1021/acs.jcim.3c01241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023]
Abstract
Cytochrome P450 3A4 (CYP3A4), a prominent member of the P450 enzyme superfamily, plays a crucial role in metabolizing various xenobiotics, including over 50% of clinically significant drugs. Evaluating CYP3A4 inhibition before drug approval is essential to avoiding potentially harmful pharmacokinetic drug-drug interactions (DDIs) and adverse drug reactions (ADRs). Despite the development of several CYP inhibitor prediction models, the primary approach for screening CYP inhibitors still relies on experimental methods. This might stem from the limitations of existing models, which only provide deterministic classification outcomes instead of precise inhibition intensity (e.g., IC50) and often suffer from inadequate prediction reliability. To address this challenge, we propose an uncertainty-guided regression model to accurately predict the IC50 values of anti-CYP3A4 activities. First, a comprehensive data set of CYP3A4 inhibitors was compiled, consisting of 27,045 compounds with classification labels, including 4395 compounds with explicit IC50 values. Second, by integrating the predictions of the classification model trained on a larger data set and introducing an evidential uncertainty method to rank prediction confidence, we obtained a high-precision and reliable regression model. Finally, we use the evidential uncertainty values as a trustworthy indicator to perform a virtual screening of an in-house compound set. The in vitro experiment results revealed that this new indicator significantly improved the hit ratio and reduced false positives among the top-ranked compounds. Specifically, among the top 20 compounds ranked with uncertainty, 15 compounds were identified as novel CYP3A4 inhibitors, and three of them exhibited activities less than 1 μM. In summary, our findings highlight the effectiveness of incorporating uncertainty in compound screening, providing a promising strategy for drug discovery and development.
Collapse
Affiliation(s)
- Ruixuan Wang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhikang Liu
- School of Mathematics and Statistics, Central South University, Changsha 410083, China
| | - Jiahao Gong
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qingping Zhou
- School of Mathematics and Statistics, Central South University, Changsha 410083, China
| | - Xiaoqing Guan
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guangbo Ge
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| |
Collapse
|
|
10
|
Wazalwar SS, Banpurkar AR, Perdih F. Synthesis, crystal structure and molecular docking study of novel isoxazole derivatives as CYP450 inhibitors in search of anticancer agents. J Biomol Struct Dyn 2023; 41:9476-9491. [PMID: 36350074 DOI: 10.1080/07391102.2022.2142667] [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: 12/03/2021] [Accepted: 10/27/2022] [Indexed: 11/11/2022]
Abstract
Synthesis of some novel isoxazole derivatives and their molecular docking with enzymes from CYP450 family carried out using erlotinib, gemcitabine and ketoconazole as reference drugs are reported in this work. Eight isoxazole derivatives of 3,4-substituted phenyl 3-chloroacrylaldehyde and one isoxazole derivative of cinnamaldehyde were synthesized. A molecular docking study of all nine compounds shows good docking score compared to standard drugs erlotinib, gemcitabine and ketoconazole. 4-OH and 4-F derivatives were found to have strong affinity for all six CYP450 proteins under study in the present work. 4-F and 3-NO2 derivatives could be a suitable lead compound inhibitor to CYP1A2 followed by 4-OH derivatives. 4-OH derivative with significant binding affinity showed encouraging inhibition of CYP1A2, CYP2C9, CYP2C8, CYP2C19 and CYP2D6. The current predictions over these nine isoxazole derivatives of 3,4-substituted phenyl 3-chloroacrylaldehyde will be needed to be further investigated in vivo and in vitro conditions to identify the optimum therapeutic efficacy. Synthesis of the isoxazole derivatives is the first known report of the Knoevenagal condensation of acrylaldehyde derivatives to form isoxazole derivatives as per the literature survey. A detailed crystal structure study of five analogues gives insight into the solid-state structural features of this new framework with isoxazole moieties.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Sachin Sudhakar Wazalwar
- Department of Applied Chemistry, Rajiv Gandhi College of Engineering, Research & Technology, Chandrapur, Maharashtra, India
| | - Anita Ravindra Banpurkar
- Department of Applied Chemistry, Rajiv Gandhi College of Engineering, Research & Technology, Chandrapur, Maharashtra, India
| | - Franc Perdih
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| |
Collapse
|
|
11
|
Aba PE, Ihedioha JI, Asuzu IU. A review of the mechanisms of anti-cancer activities of some medicinal plants-biochemical perspectives. J Basic Clin Physiol Pharmacol 2023; 34:419-428. [PMID: 34936737 DOI: 10.1515/jbcpp-2021-0257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/28/2021] [Indexed: 06/14/2023]
Abstract
Cancer is a disease resulting in unbridled growth of cells due to dysregulation in the balance of cell populations. Various management procedures in handling cases of cancer are not without their adverse side effects on the normal cells. Medicinal plants/herbs have been in use in the management of various ailments, including cancer, for a long time. Medicinal plants have been credited with wide safety margins, cost effectiveness, availability and diverse activities. This study reviewed various mechanisms of anti-cancer activities of some medicinal plants from a biochemical perspective. The mechanisms of anti-cancer activities of plant compounds addressed in this article include induction of apoptosis, anti-angiogenic effects, anti-metastasis, inhibition of cell cycle, inhibition of DNA destruction and effects on key enzymes, cytotoxic and anti-oxidant effects. The anti-cancer activities of some of the plants involve more than one mechanism.
Collapse
Affiliation(s)
- Patrick E Aba
- Department of Veterinary Physiology and Pharmacology, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - John I Ihedioha
- Department of Veterinary Pathology and Microbiology, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Isaac U Asuzu
- Department of Veterinary Physiology and Pharmacology, University of Nigeria, Nsukka, Enugu State, Nigeria
| |
Collapse
|
|
12
|
Modulation of cytochrome P450 1A (CYP1A) enzymes by monomethylmonothioarsonic acid (MMMTA V) in vivo and in vitro. Chem Biol Interact 2023; 376:110447. [PMID: 36893905 DOI: 10.1016/j.cbi.2023.110447] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Inorganic arsenic (iAs) is a natural toxicant which, upon entering the biosphere, undergoes extensive biotransformation and becomes a portal for generating various organic intermediates/products. The chemical diversity of iAs-derived organoarsenicals (oAs) is accompanied by varying degree of toxicity that can be held responsible, at least partly, for the overall health outcome of the originally encountered parent inorganic molecule. Such toxicity may originate from arsenicals ability to modulate cytochrome P450 1A (CYP1A) enzymes, whose activity is critical in activating/detoxifying procarcinogens. In this study, we evaluated the effect of monomethylmonothioarsonic acid (MMMTAV) on CYP1A1 and CYP1A2 in absence and presence of their inducer; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, C57BL/6 mice were intraperitoneally injected with 12.5 mg/kg MMMTAV, with or without 15 μg/kg TCDD for 6 and 24 h. Moreover, murine Hepa-1c1c7 and human HepG2 cells were treated with MMMTAV (1, 5, and 10 μM), with or without 1 nM TCDD for 6 and 24 h. MMMTAV significantly inhibited TCDD-mediated induction of CYP1A1 mRNA, both in vivo and in vitro. This effect was attributed to decreased transcriptional activation of CYP1A regulatory element. Interestingly, MMMTAV significantly increased TCDD-induced CYP1A1 protein and activity in C57BL/6 mice and Hepa-1c1c7 cells, while both were significantly inhibited by MMMTAV treatment in HepG2 cells. CYP1A2 mRNA, protein and activity induced by TCDD were significantly increased by MMMTAV co-exposure. MMMTAV had no effect on CYP1A1 mRNA stability or protein stability and did not alter their half-lives. At basal level, only CYP1A1 mRNA was significantly decreased in MMMTAV-treated Hepa-1c1c7 cells. Our findings show that MMMTAV exposure potentiates procarcinogen-induced catalytic activity of both CYP1A1 and CYP1A2 in vivo. This effect entails excessive activation of such procarcinogens upon co-exposure, with potentially negative health-related outcomes.
Collapse
|
|
13
|
Trampuž M, Žnidarič M, Gallou F, Časar Z. Does the Red Shift in UV-Vis Spectra Really Provide a Sensing Option for Detection of N-Nitrosamines Using Metalloporphyrins? ACS OMEGA 2023; 8:1154-1167. [PMID: 36643536 PMCID: PMC9835193 DOI: 10.1021/acsomega.2c06615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/08/2022] [Indexed: 06/17/2023]
Abstract
N-nitrosamines are widespread cancerogenic compounds in human environment, including water, tobacco products, food, and medicinal products. Their presence in pharmaceuticals has recently led to several recalls of important medicines from the market, and strict controls and tight limits of N-nitrosamines are now required. Analytical determination of N-nitrosamines is expensive, laborious, and time-inefficient making development of simpler and faster techniques for their detection crucial. Several reports published in the previous decade have demonstrated that cobalt porphyrin-based chemosensors selectively bind N-nitrosamines, which produces a red shift of characteristic Soret band in UV-Vis spectra. In this study, a thorough re-evaluation of metalloporphyrin/N-nitrosamine adducts was performed using various characterization methods. Herein, we demonstrate that while N-nitrosamines can interact directly with cobalt-based porphyrin complexes, the red shift in UV-Vis spectra is not selectively assured and might also result from the interaction between impurities in N-nitrosamines and porphyrin skeleton or interaction of other functional groups within the N-nitrosamine structure and the metal ion within the porphyrin. We show that pyridine nitrogen is the interacting atom in tobacco-specific N-nitrosamines (TSNAs), as pyridine itself is an active ligand and not the N-nitrosamine moiety. When using Co(II) porphyrins as chemosensors, acidic and basic impurities in dialkyl N-nitrosamines (e.g., formic acid, dimethylamine) are also UV-Vis spectra red shift-producing species. Treatment of these N-nitrosamines with K2CO3 prevents the observed UV-Vis phenomena. These results imply that cobalt-based metalloporphyrins cannot be considered as selective chemosensors for UV-Vis detection of N-nitrosamine moiety-containing species. Therefore, special caution in interpretation of UV-Vis red shift for chemical sensors is suggested.
Collapse
Affiliation(s)
- Marko Trampuž
- Lek
Pharmaceuticals d.d., Sandoz Development
Center Slovenia, Kolodvorska
27, 1234 Mengeš, Slovenia
| | - Mateja Žnidarič
- Lek
Pharmaceuticals d.d., Sandoz Development
Center Slovenia, Kolodvorska
27, 1234 Mengeš, Slovenia
| | - Fabrice Gallou
- Chemical
and Analytical Development, Novartis Pharma
AG, Basel 4056, Switzerland
| | - Zdenko Časar
- Lek
Pharmaceuticals d.d., Sandoz Development
Center Slovenia, Kolodvorska
27, 1234 Mengeš, Slovenia
- Chair
of Medicinal Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
| |
Collapse
|
|
14
|
Potential Role of Oxidative Stress in the Production of Volatile Organic Compounds in Obesity. Antioxidants (Basel) 2023; 12:antiox12010129. [PMID: 36670991 PMCID: PMC9854577 DOI: 10.3390/antiox12010129] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Obesity is associated with numerous health issues such as sleep disorders, asthma, hepatic dysfunction, cancer, renal dysfunction, diabetes, cardiovascular complications, and infertility. Previous research has shown that the distribution of excess body fat, rather than excess body weight, determines obesity-related risk factors. It is widely accepted that abdominal fat is a serious risk factor for illnesses associated with obesity and the accumulation of visceral fat promotes the release of pro-oxidants, pro-inflammatory, and reactive oxygen species (ROS). The metabolic process in the human body produces several volatile organic compounds (VOCs) via urine, saliva, breath, blood, skin secretions, milk, and feces. Several studies have shown that VOCs are released by the interaction of ROS with underlying cellular components leading to increased protein oxidation, lipid peroxidation, or DNA damage. These VOCs released via oxidative stress in obese individuals may serves as a biomarker for obesity-related metabolic alterations and disease. In this review, we focus on the relationship between oxidative stress and VOCs in obesity.
Collapse
|
|
15
|
Assessment of a Diverse Array of Nitrite Scavengers in Solution and Solid State: A Study of Inhibitory Effect on the Formation of Alkyl-Aryl and Dialkyl N-Nitrosamine Derivatives. Processes (Basel) 2022. [DOI: 10.3390/pr10112428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The ubiquitous presence of mutagenic and potentially carcinogenic N-nitrosamine impurities in medicines has become a major issue in the pharmaceutical industry in recent years. Rigorous mitigation strategies to limit their amount in drug products are, therefore, needed. The removal of nitrite, which is a prerequisite reagent for the N-nitrosation of amines, has been acknowledged as one of the most promising strategies. We have conducted an extensive literature search to identify nineteen structurally diverse nitrite scavengers and screened their activity experimentally under pharmaceutically relevant conditions. In the screening phase, we have identified six compounds that proved to have the best nitrite scavenging properties: ascorbic acid (vitamin C), sodium ascorbate, maltol, propyl gallate, para-aminobenzoic acid (PABA), and l-cysteine. These were selected for investigation as inhibitors of the formation of N-methyl-N-nitrosoaniline (NMA) from N-methylaniline and N-nitroso-N’-phenylpiperazine (NPP) from N-phenylpiperazine in both solution and model tablets. Much faster kinetics of NMA formation compared to NPP was observed, but the former was less stable at high temperatures. Vitamin C, PABA, and l-cysteine were recognized as the most effective inhibitors under most studied conditions. The nitrite scavenging activity does not directly translate into N-nitrosation inhibitory effectiveness, indicating other reaction pathways may take place. The study presents an important contribution to identifying physiologically acceptable chemicals that could be added to drugs to prevent N-nitrosation during manufacture and storage.
Collapse
|
|
16
|
Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site. Int J Mol Sci 2022; 23:ijms232012591. [PMID: 36293445 PMCID: PMC9604483 DOI: 10.3390/ijms232012591] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 11/29/2022] Open
Abstract
Cytochrome P450 3A4 (CYP3A4) is a major human drug-metabolizing enzyme, notoriously known for its extreme substrate promiscuity, allosteric behavior, and implications in drug–drug interactions. Despite extensive investigations, the mechanism of ligand binding to CYP3A4 is not fully understood. We determined the crystal structure of CYP3A4 complexed with fluorol, a small fluorescent dye that can undergo hydroxylation. In the structure, fluorol associates to the substrate channel, well suited for the binding of planar polyaromatic molecules bearing polar groups, through which stabilizing H-bonds with the polar channel residues, such as Thr224 and Arg372, can be established. Mutagenesis, spectral, kinetic, and functional data confirmed the involvement but not strict requirement of Thr224 for the association of fluorol. Collectively, our data identify the substrate channel as a high-affinity ligand binding site and support the notion that hydrophobic ligands first dock to the nearby peripheral surface, before migrating to the channel and, subsequently, into the active site.
Collapse
|
|
17
|
El-Ghiaty MA, Alqahtani MA, El-Kadi AOS. Down-regulation of hepatic cytochromes P450 1A1 and 1A2 by arsenic trioxide (ATO) in vivo and in vitro: A role of heme oxygenase 1. Chem Biol Interact 2022; 364:110049. [PMID: 35872050 DOI: 10.1016/j.cbi.2022.110049] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/03/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
Abstract
Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 μg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 μM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination.
Collapse
Affiliation(s)
- Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
| |
Collapse
|
|
18
|
Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment. Int J Mol Sci 2022; 23:ijms23137291. [PMID: 35806297 PMCID: PMC9266530 DOI: 10.3390/ijms23137291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 02/04/2023] Open
Abstract
Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure–activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers’ length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.
Collapse
|
|
19
|
Rusni S, Sassa M, Takagi T, Kinoshita M, Takehana Y, Inoue K. Establishment of cytochrome P450 1a gene-knockout Javanese medaka, Oryzias javanicus, which distinguishes toxicity modes of the polycyclic aromatic hydrocarbons, pyrene and phenanthrene. MARINE POLLUTION BULLETIN 2022; 178:113578. [PMID: 35344733 DOI: 10.1016/j.marpolbul.2022.113578] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 03/08/2022] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
Cytochrome P450 1a (Cyp1a) is an important enzyme for metabolism of organic pollutants. To understand its reaction to polycyclic aromatic hydrocarbons (PAHs), we knocked out this gene in a marine model fish, Javanese medaka, Oryzias javanicus, using the CRISPR/Cas 9 system. A homozygous mutant (KO) strain with a four-base deletion was established using an environmental DNA (eDNA)-based genotyping technique. Subsequently, KO, heterozygous mutant (HT), and wild-type (WT) fish were exposed to model pollutants, pyrene and phenanthrene, and survivorship and swimming behavior were analyzed. Compared to WT, KO fish were more sensitive to pyrene, suggesting that Cyp1a transforms pyrene into less toxic metabolites. Conversely, WT fish were sensitive to phenanthrene, suggesting that metabolites transformed by Cyp1a are more toxic than the original compound. HT fish showed intermediate results. Thus, comparative use of KO and WT fish can distinguish modes of pollutant toxicity, providing a deeper understanding of fish catabolism of environmental pollutants.
Collapse
Affiliation(s)
- Suhaila Rusni
- Atmosphere and Ocean Research Institute, The University of Tokyo, Kashiwa, Japan; Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
| | - Mieko Sassa
- Atmosphere and Ocean Research Institute, The University of Tokyo, Kashiwa, Japan.
| | - Toshiyuki Takagi
- Atmosphere and Ocean Research Institute, The University of Tokyo, Kashiwa, Japan.
| | | | - Yusuke Takehana
- Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
| | - Koji Inoue
- Atmosphere and Ocean Research Institute, The University of Tokyo, Kashiwa, Japan; Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
| |
Collapse
|
|
20
|
Issitt T, Wiggins L, Veysey M, Sweeney S, Brackenbury W, Redeker K. Volatile compounds in human breath: critical review and meta-analysis. J Breath Res 2022; 16. [PMID: 35120340 DOI: 10.1088/1752-7163/ac5230] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/04/2022] [Indexed: 11/12/2022]
Abstract
Volatile compounds contained in human breath reflect the inner workings of the body. A large number of studies have been published that link individual components of breath to disease, but diagnostic applications remain limited, in part due to inconsistent and conflicting identification of breath biomarkers. New approaches are therefore required to identify effective biomarker targets. Here, volatile organic compounds have been identified in the literature from four metabolically and physiologically distinct diseases and grouped into chemical functional groups (e.g. - methylated hydrocarbons or aldehydes; based on known metabolic and enzymatic pathways) to support biomarker discovery and provide new insight on existing data. Using this functional grouping approach, principal component analysis doubled explanatory capacity from 19.1% to 38% relative to single individual compound approaches. Random forest and linear discriminant analysis reveal 93% classification accuracy for cancer. This review and meta-analysis provides insight for future research design by identifying volatile functional groups associated with disease. By incorporating our understanding of the complexities of the human body, along with accounting for variability in methodological and analytical approaches, this work demonstrates that a suite of targeted, functional volatile biomarkers, rather than individual biomarker compounds, will improve accuracy and success in diagnostic research and application.
Collapse
Affiliation(s)
- Theo Issitt
- Biology, University of York, University of York, York, York, YO10 5DD, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Laura Wiggins
- Biology, University of York, University of York, York, York, YO10 5DD, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Martin Veysey
- The University of Newcastle, School of Medicine & Public Health, Callaghan, New South Wales, 2308, AUSTRALIA
| | - Sean Sweeney
- Biology, University of York, University of York, York, York, YO10 5DD, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - William Brackenbury
- Biology, University of York, University of York, York, York, YO10 5DD, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Kelly Redeker
- Biology, University of York, Biology Dept. University of York, York, York, North Yorkshire, YO10 5DD, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| |
Collapse
|
|
21
|
Abstract
Heterocyclic aromatic amines (HAAs) are mainly formed in the pyrolysis process during high-temperature cooking of meat. Meat consumption is very typical of the western diet, and the amount of meat consumption in the eastern countries is growing rapidly; HAAs represents widespread exposure. HAAs are classified as possible human carcinogens; numerous epidemiological studies have demonstrated regular consumption of meat with HAAs as risk factor for cancers. Specific HAAs have received major attention. For example, 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine has been extensively studied as a genotoxicant and mutagen, with emergent literature on neurotoxicity. Harmane has been extensively studied for a role in essential tremors and potentially Parkinson's disease (PD). Harmane levels have been demonstrated to be elevated in blood and brain in essential tremor patients. Meat consumption has been implicated in the etiology of neurodegenerative diseases; however, the role of toxicants formed during meat preparation has not been studied. Epidemiological studies are currently examining the association between HAAs and risk of neurodegenerative diseases such as essential tremors and PD. Studies from our laboratory and others have provided strong evidence that HAA exposure produces PD and Alzheimer's disease-relevant neurotoxicity in cellular and animal models. In this review, we summarize and critically evaluate previous studies on HAA-induced neurotoxicity and the molecular basis of potential neurotoxic effects of HAAs. The available studies provide strong support for the premise that HAAs may impact neurological function and that addressing gaps in understanding of adverse neurological outcomes is critical to determine whether these compounds are modifiable risk factors.
Collapse
Affiliation(s)
- Tauqeerunnisa Syeda
- School of Health Sciences, Purdue University, West Lafayette, Indiana 47907, United States
- Purdue Institute for Integrative Neurosciences, Purdue University, West Lafayette, Indiana 47907, United States
| | - Jason R Cannon
- School of Health Sciences, Purdue University, West Lafayette, Indiana 47907, United States
- Purdue Institute for Integrative Neurosciences, Purdue University, West Lafayette, Indiana 47907, United States
| |
Collapse
|
|
22
|
Bussy U, Boisseau R, Croyal M, Temgoua RCT, Boujtita M. In-line formation and identification of toxic reductive metabolites of aristolochic acid using electrochemistry mass spectrometry coupling. Anal Bioanal Chem 2022; 414:2363-2370. [DOI: 10.1007/s00216-022-03874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/08/2021] [Accepted: 01/04/2022] [Indexed: 11/01/2022]
|
|
23
|
Eftekhar SP, Kazemi S, Moghadamnia AA. Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro. Hum Exp Toxicol 2022; 41:9603271221145422. [PMID: 36510676 DOI: 10.1177/09603271221145422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration (Cmax), area under the curve (AUC), and time of maximum concentration (Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.
Collapse
Affiliation(s)
- Seyed Parsa Eftekhar
- Department of Pharmacology and Toxicology, School of Medicine, 114456Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, 114456Babol University of Medical Sciences, Babol, Iran
| | - Ali Akbar Moghadamnia
- Department of Pharmacology and Toxicology, School of Medicine, 114456Babol University of Medical Sciences, Babol, Iran
| |
Collapse
|
|
24
|
Ibrahem SQ, Ahmed HQ, Amin KM. Genetic Variations in Cytochrome P450 1A1 and 1B1 Genes in a Cohort of Patients from Iraq Diagnosed with Breast Cancer. Breast Cancer (Auckl) 2021; 15:11782234211050727. [PMID: 34671182 PMCID: PMC8521753 DOI: 10.1177/11782234211050727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 09/14/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most prevalent malignant neoplasm in females. Genetic variations in the xenobiotic metabolising cytochrome enzymes; Family 1 Subfamily A Member 1 (CYP1A1) and Family 1 Subfamily B Member 1 (CYP1B1) might play a role in the individual susceptibility to breast cancer and its prognosis. The goal of this study is to estimate the incidence of single nucleotide polymorphisms (SNPs) in CYP1A1 (rs1048943, Ile462VaI, and rs4646903/MSP1) and in CYP1B1 (rs1056836, Leu432Val) genes in patients with breast cancer. This case-control study included 180 female patients with breast cancer and 180 healthy control subjects from Kirkuk/Iraq. Genomic DNA was extracted from venous blood samples and tested for SNPs by the direct DNA sequencing technique. A statistical analysis was done to identify if there is any association between SNPs and the increasing odd of breast cancer and its stage, grade and molecular subtype at diagnosis. The common (reference) genotype of CYP1A1 gene rs1048943 is AA. The AG and GG variant genotypes were significantly more common in the breast cancer patients and conferred an increased odd of breast cancer and its later stages (stages III and IV) and poor differentiation (P < .01) but not with the molecular subtypes. The common genotype of CYP1A1 rs4646903 is TT. The variant genotypes TC and CC are not associated either with increased risk of breast cancer (P > .05) or with its stage, grade or molecular subtypes (P > .05). The GG genotype of CYP1B1 rs1056836 was the common genotype. The CG and CC variant genotypes were not associated with the increased risks of breast cancer (P > .05) or its stage, grade or molecular subtypes (P > .05). In conclusion, variants genotypes of CYP1A1 rs1048943 might play a role in breast cancer pathogenesis and prognosis and can have a place in cancer screening and tailored medicine in the future in the Iraqi population. Future larger scale studies including other genes might help to better understand the role of the SNP in breast risk and its prognosis.
Collapse
Affiliation(s)
- Salih Q Ibrahem
- Department of Biochemistry, College of Medicine, Kirkuk University, Kirkuk, Iraq
| | - Hussien Q Ahmed
- Department of Surgery, College of Medicine, Kirkuk University, Kirkuk, Iraq
| | - Khalida M Amin
- Department of Obstetrics and Gynaecology, College of Medicine, Kirkuk University, Kirkuk, Iraq
| |
Collapse
|
|
25
|
Relationship between lung function and lung cancer risk: a pooled analysis of cohorts plus Mendelian randomization study. J Cancer Res Clin Oncol 2021; 147:2837-2849. [PMID: 34318357 DOI: 10.1007/s00432-021-03619-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 03/25/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Since little consensus has been reached on whether milder reduction in forced expiratory volume in 1 s (FEV1) increases lung cancer incidence, we conducted a meta-analysis and performed Mendelian randomization (MR) analysis to explore the association and causal relationship between FEV1 and lung cancer incidence. METHODS We conducted a comprehensive search from PubMed, Medline, EMBASE, and Cochrane Library databases as of February 2020. MR analysis was performed using summary data obtained from two large consortia [International Lung Cancer Consortium (ILCCO) and Neale Lab] to assess the possible causality between FEV1 and lung cancer risk. RESULTS Eight studies involving 88,743 cases were included. The incidence of lung cancer increased with decreasing FEV1.The combined odds ratio (OR) of decreased FEV1 for lung cancer incidence was 1.91 [95% confidence interval (CI) 1.67-2.19; P < 0.001]. Compared with the highest quintile of FEV1 (quintile 5, > 100% of predicted), the OR was 3.06 (95% CI 2.20-4.24; P < 0.001) for quintile 1 (< 70% of predicted), 1.89 (95% CI 1.50-2.38; P < 0.001) for quintile 2 (70-80% of predicted), 1.53 (95% CI 1.31-1.79; P < 0.001) for quintile 3 (80-90% of predicted), and 1.64 (95% CI 1.18-2.28; P = 0.003) for quintile 4 (90-100% of predicted). In subgroup meta-analysis, the correlation between FEV1 and lung cancer risk was different among men (OR = 1.74; 95% CI 1.49-2.03; P < 0.001) and women (OR = 2.80; 95% CI 1.87-4.19; P < 0.001). However, MR analysis showed no causality between the FEV1 and lung cancer risk (OR = 1.199; 95% CI 0.958-1.500; P = 0.114). CONCLUSION FEV1 is likely to be a predictor of lung cancer, especially for women. However, genetically decreased FEV1 is not causally correlated with lung cancer incidence.
Collapse
|
|
26
|
Ogbede JU, Giaever G, Nislow C. A genome-wide portrait of pervasive drug contaminants. Sci Rep 2021; 11:12487. [PMID: 34127714 PMCID: PMC8203678 DOI: 10.1038/s41598-021-91792-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/25/2021] [Indexed: 11/08/2022] Open
Abstract
Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitness defects in strains lacking genes of the arginine pathway, we tested several N-nitrosamine metabolites (methylamine, ethylamine and formamide), and found they also affected arginine pathway mutants. Notably, each of these metabolites has the potential to produce ammonium ions during their biotransformation. We directly tested the role of ammonium ions in N-nitrosamine toxicity by treatment with ammonium sulfate and we found that ammonium sulfate also caused a growth defect in arginine pathway deletion strains. Formaldehyde, a metabolite produced from NDMA, methylamine and formamide, and which is known to cross-link free amines, perturbed deletion strains involved in chromatin remodeling and DNA repair pathways. Finally, co-administration of N-nitrosamines with ascorbic or ferulic acid did not relieve N-nitrosamine toxicity. In conclusion, we used parallel deletion mutant analysis to characterize the genes and pathways affected by exposure to N-nitrosamines and related compounds, and provide the data in an accessible, queryable database.
Collapse
Affiliation(s)
- Joseph Uche Ogbede
- Genome Science & Technology Graduate Program, University of British Columbia, Vancouver, Canada
| | - Guri Giaever
- Faculty of Pharmaceutical Science, University of British Columbia, Vancouver, Canada
| | - Corey Nislow
- Genome Science & Technology Graduate Program, University of British Columbia, Vancouver, Canada.
- Faculty of Pharmaceutical Science, University of British Columbia, Vancouver, Canada.
| |
Collapse
|
|
27
|
Toupin N, Steinke SJ, Nadella S, Li A, Rohrabaugh TN, Samuels ER, Turro C, Sevrioukova IF, Kodanko JJ. Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4. J Am Chem Soc 2021; 143:9191-9205. [PMID: 34110801 DOI: 10.1021/jacs.1c04155] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru(tpy)(L)(6)]Cl2 (tpy = 2,2':6',2″-terpyridine) with L = 6,6'-dimethyl-2,2'-bipyridine (Me2bpy; 8), dimethylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine (Me2Ph2dppn; 11), [Ru(tpy)(Me2bpy)(4)]Cl2 (7) and [Ru(tpy)(Me2dppn)(4)]Cl2 (9). Photochemical release of 4 or 6 from 7-11 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 9-11 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.
Collapse
Affiliation(s)
- Nicholas Toupin
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Sean J Steinke
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Sandeep Nadella
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Ao Li
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
| | - Thomas N Rohrabaugh
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | | | - Claudia Turro
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | | | - Jeremy J Kodanko
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.,Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, United States
| |
Collapse
|
|
28
|
Léonard E, Fayeulle A. Azo-Dyes-Grafted Oligosaccharides-From Synthesis to Applications. Molecules 2021; 26:3063. [PMID: 34063753 PMCID: PMC8196571 DOI: 10.3390/molecules26113063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 11/16/2022] Open
Abstract
Azobenzenes are photochromic molecules that possess a large range of applications. Their syntheses are usually simple and fast, and their purifications can be easy to perform. Oligosaccharide is also a wide family of biopolymer constituted of linear chain of saccharides. It can be extracted from biomass, as for cellulose, being the principal constituent of plant cell wall, or it can be enzymatically produced as for cyclodextrins, having properties not far from cellulose. Combining these two materials families can afford interesting applications such as controlled drug-release systems, photochromic liquid crystals, photoresponsive films or even fluorescent indicators. This review will compile the different syntheses of azo-dyes-grafted oligosaccharides, and will show their various applications.
Collapse
Affiliation(s)
- Estelle Léonard
- Université de Technologie de Compiègne, ESCOM, TIMR (Integrated Transformations of Renewable Matter), Centre de Recherche Royallieu, CS 60 319, CEDEX, 60203 Compiègne, France;
| | | |
Collapse
|
|
29
|
Kumari R, Dhankhar P, Dalal V. Structure-based mimicking of hydroxylated biphenyl congeners (OHPCBs) for human transthyretin, an important enzyme of thyroid hormone system. J Mol Graph Model 2021; 105:107870. [PMID: 33647754 DOI: 10.1016/j.jmgm.2021.107870] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/22/2021] [Accepted: 02/15/2021] [Indexed: 01/06/2023]
Abstract
In humans, transthyretin (hTTR) is a plasma protein act as a transporter of thyroxine (T4) in the blood. Polychlorinated biphenyls (PCBs) are used in coolants, transformers, plasticizers, and pesticide extenders, etc. due to their physical properties, chemical stability, and dielectric properties. Cytochrome P450 can oxidize the PCBs into hydroxylated PCBs (OHPCBs) which can further interact with hTTR results in hepatoxicity, loss of metabolic rate, memory problems, and neurotoxicity. Molecular docking results show that OHPCBs bind at the active site of hTTR with a more binding affinity as compared to T4. Further, molecular dynamics simulation has been done to confirm the stability of hTTR-OHPCBs complexes. Several analysis parameters like RMSD, RMSF, Rg, SASA, hydrogen bonds numbers, PCA, and FEL revealed that binding of OHPCBs with hTTR results in the formation of stable hTTR-OHPCBs complexes. Individual residues decomposition analysis confirms that Lys15, Leu17, Ala108, Ala109, Leu110, Ser117, and Thr119 of hTTR plays a major role in the binding of OHPCBs to form the lower energy hTTR-OHPCBs complexes. Molecular docking and simulations results emphasize that OHPCBs can efficiently bind at the active site of hTTR, which further leads to inhibition of transportation of T4 in human blood.
Collapse
Affiliation(s)
- Reena Kumari
- Department of Mathematics and Statistics, Swami Vivekanand Subharti University, Meerut, 250005, India
| | - Poonam Dhankhar
- Department of Biotechnology, IIT Roorkee, Uttarakhand, 247667, India
| | - Vikram Dalal
- Department of Biotechnology, IIT Roorkee, Uttarakhand, 247667, India.
| |
Collapse
|
|
30
|
Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength. Int J Mol Sci 2021; 22:ijms22020852. [PMID: 33467005 PMCID: PMC7830545 DOI: 10.3390/ijms22020852] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure–activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1–phenyl/R2–indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl–ethyl to pyridyl–propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.
Collapse
|
|
31
|
CYP2D6 gene polymorphisms and breast cancer risk in Moroccan population: A case-control study. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
|
|
32
|
Donato MT, Castell JV, Gómez-Lechón MJ. The Coumarin 7-Hydroxylation Microassay in Living Hepatic Cells in Culture. Altern Lab Anim 2020. [DOI: 10.1177/026119299802600206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Coumarin 7-hydroxylation was evaluated in hepatic cells from various species, cultured in 96-well plates. This microassay involved incubating living cultured cells with the substrate, followed by fluorimetric quantification of the product released into the culture supernatant, after hydrolysis of the conjugates of 7-hydroxycoumarin that were formed. Fluorescence was measured directly in the wells by using a microplate fluorescence reader. The major advantages of this technique are its simplicity and automation, the small number of cells required, the reduction in sample handling and assay time, and the possibility of performing repeated assays with the same cell monolayer, since no injury to cells is detectable during the assay. By using this microassay, it was shown that human hepatocytes hydroxylated coumarin at higher rates than did rabbit, dog or rat hepatocytes, and that no appreciable metabolic activity was observed in hepatoma cells (Hep G2 and FaO). In addition, methoxsalen was found to be a potent inhibitor of cytochrome P4502A6 activity in living human hepatocytes.
Collapse
Affiliation(s)
- M. Teresa Donato
- Unidad de Hepatologia Experimental, Centro de Investigation, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain
| | - José V. Castell
- Unidad de Hepatologia Experimental, Centro de Investigation, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain
| | - Maria José Gómez-Lechón
- Unidad de Hepatologia Experimental, Centro de Investigation, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain
| |
Collapse
|
|
33
|
Yonemura K, Ariyasu S, Stanfield JK, Suzuki K, Onoda H, Kasai C, Sugimoto H, Aiba Y, Watanabe Y, Shoji O. Systematic Evolution of Decoy Molecules for the Highly Efficient Hydroxylation of Benzene and Small Alkanes Catalyzed by Wild-Type Cytochrome P450BM3. ACS Catal 2020. [DOI: 10.1021/acscatal.0c01951] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Kai Yonemura
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Shinya Ariyasu
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Joshua Kyle Stanfield
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Kazuto Suzuki
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Hiroki Onoda
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Chie Kasai
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Hiroshi Sugimoto
- RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo, Hyogo 679-5148, Japan
- Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori, Ako, Hyogo 678-1297, Japan
- Core Research for Evolutional Science and Technology (Japan), Science and Technology Agency, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Yuichiro Aiba
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Yoshihito Watanabe
- Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Osami Shoji
- Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
- Core Research for Evolutional Science and Technology (Japan), Science and Technology Agency, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
| |
Collapse
|
|
34
|
Chen D, Liu JR, Cheng Y, Cheng H, He P, Sun Y. Metabolism of Rhaponticin and Activities of its Metabolite, Rhapontigenin: A Review. Curr Med Chem 2020; 27:3168-3186. [DOI: 10.2174/0929867326666190121143252] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 11/22/2018] [Accepted: 12/28/2018] [Indexed: 12/13/2022]
Abstract
Rhaponticin is a stilbenoid glucoside compound, found in medicinal plant of rhubarb
rhizomes. Rhapontigenin (RHAG), the stilbene aglycone metabolite of rhaponticin, has
shown various biological activities including anticancer activities to act a potential human cytochrome
P450 inhibitor, antihyperlipidemic effect, anti-allergic action, antioxidant and antibacterial
activities. Moreover, it was reported to scavenge intracellular Reactive Oxygen Species
(ROS), the 1,1-Diphenyl-2-Picrylliydrazyl (DPPH) radical, and Hydrogen Peroxide
(H2O2). Meanwhile, RHAG exhibited the inhibitory activity for the synthesis of DNA, RNA
and protein, and also presented the capacity of inducing morphological changes and apoptosis
of C. albicans. Here, the structure, pharmacokinetics, pharmacological effects as well as underlying
mechanisms of rhaponticin and its metabolite, RHAG, have been extensively reviewed.
This review will provide a certain reference value for developing the therapeutic drug
of rhaponticin or RHAG.
Collapse
Affiliation(s)
- Dan Chen
- School of Food Science and Technology, School of Chemical Engineering, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China
| | - Jing-Ru Liu
- School of Life Science, Northwest University, Xi’an, Shaanxi 710069, China
| | - Yanjin Cheng
- School of Mathematics and Statistics, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China
| | - Hua Cheng
- School of Food Science and Technology, School of Chemical Engineering, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China
| | - Ping He
- School of Food Science and Technology, School of Chemical Engineering, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China
| | - Yang Sun
- School of Food Science and Technology, School of Chemical Engineering, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China
| |
Collapse
|
|
35
|
Yun BH, Guo J, Bellamri M, Turesky RJ. DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans. MASS SPECTROMETRY REVIEWS 2020; 39:55-82. [PMID: 29889312 PMCID: PMC6289887 DOI: 10.1002/mas.21570] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/25/2018] [Indexed: 05/18/2023]
Abstract
Hazardous chemicals in the environment and diet or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. In addition, reactive intermediates can be generated in the body through oxidative stress and damage the genome. The identification and measurement of DNA adducts are required for understanding exposure and the causal role of a genotoxic chemical in cancer risk. Over the past three decades, 32 P-postlabeling, immunoassays, gas chromatography/mass spectrometry, and liquid chromatography/mass spectrometry (LC/MS) methods have been established to assess exposures to chemicals through measurements of DNA adducts. It is now possible to measure some DNA adducts in human biopsy samples, by LC/MS, with as little as several milligrams of tissue. In this review article, we highlight the formation and biological effects of DNA adducts, and highlight our advances in human biomonitoring by mass spectrometric analysis of formalin-fixed paraffin-embedded tissues, untapped biospecimens for carcinogen DNA adduct biomarker research.
Collapse
Affiliation(s)
- Byeong Hwa Yun
- Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, 2231 6 St. SE, Minneapolis, Minnesota, 55455, United States
| | - Jingshu Guo
- Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, 2231 6 St. SE, Minneapolis, Minnesota, 55455, United States
| | - Medjda Bellamri
- Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, 2231 6 St. SE, Minneapolis, Minnesota, 55455, United States
| | - Robert J. Turesky
- Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, 2231 6 St. SE, Minneapolis, Minnesota, 55455, United States
| |
Collapse
|
|
36
|
Chu P, He L, Zhu D, Huang R, Liao L, Li Y, Zhu Z, Wang Y. Identification, expression and functional characterisation of CYP1A in grass carp (Ctenopharyngodon idella). FISH & SHELLFISH IMMUNOLOGY 2019; 95:35-43. [PMID: 31610292 DOI: 10.1016/j.fsi.2019.10.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 10/08/2019] [Accepted: 10/09/2019] [Indexed: 06/10/2023]
Abstract
In mammal, CYP1A has attracted special attention due to its important roles in the oxidative metabolism. In fish, the researches on CYP1A are more focus on its roles in pollution in water environments, but the immune function is unclear. In the study, CiCYP1A gene was cloned from grass carp (Ctenopharyngodon idella). Tissue distribution exhibited an overwhelmingly high basal expression levels in the liver. After GCRV infection, CiCYP1A showed a potent response, indicating CiCYP1A was involved in GCRV-induced immunity. Subcellular localisation showed CiCYP1A was distributed in the cytoplasm. Besides, dual-luciferase activity assays revealed CYP1A was relevant for IFN-I signaling pathway modulation, furthermore, overexpressed CYP1A potently suppressed the mRNA expression of IRF3 and IFN-I but not IRF7. The results provide new sights into exploring immune function of CiCYP1A in teleosts.
Collapse
Affiliation(s)
- Pengfei Chu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Libo He
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Denghui Zhu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Rong Huang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Lanjie Liao
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Yongming Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Zuoyan Zhu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Yaping Wang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China.
| |
Collapse
|
|
37
|
Salazar-González RA, Zhang X, Doll MA, Lykoudi A, Hein DW. Role of the human N-acetyltransferase 2 genetic polymorphism in metabolism and genotoxicity of 4, 4'-methylenedianiline. Arch Toxicol 2019; 93:2237-2246. [PMID: 31292670 PMCID: PMC6713601 DOI: 10.1007/s00204-019-02516-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/04/2019] [Indexed: 01/06/2023]
Abstract
4, 4'-Methylenedianiline (MDA) is used extensively as a curing agent in the production of elastomers and is classified as reasonably anticipated to be a human carcinogen based on sufficient evidence in animal experiments. Human N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the N-acetylation of aromatic amines and NAT2 is subjected to a common genetic polymorphism in human populations separating individuals into rapid, intermediate, and slow acetylator phenotypes. Although MDA is known to undergo N-acetylation to mono- and di-acetyl metabolites, very little is known regarding whether this metabolism is subject to the NAT2 genetic polymorphism. We investigated the N-acetylation of MDA by recombinant human NAT1, NAT2, genetic variants of NAT2, and cryoplateable human hepatocytes obtained from rapid, intermediate and slow acetylators. MDA N-acetylation was catalyzed by both recombinant human NAT1 and NAT2 exhibiting a fivefold higher affinity for human NAT2. N-acetylation of MDA was acetylator genotype dependent as evidenced via its N-acetylation by recombinant human NAT2 genetic variants or by cryoplateable human hepatocytes. MDA N-acetylation to the mono-acetyl or di-acetyl-MDA was highest in rapid, lower in intermediate, and lowest in slow acetylator human hepatocytes. MDA-induced DNA damage in the human hepatocytes was dose-dependent and also acetylator genotype dependent with highest levels of DNA damage in rapid, lower in intermediate, and lowest in slow acetylator human hepatocytes under the same MDA exposure level. In summary, the N-acetylation of MDA by recombinant human NAT2 and cryopreserved human hepatocytes support an important role for the NAT2 genetic polymorphism in modifying MDA metabolism and genotoxicity and potentially carcinogenic risk.
Collapse
Affiliation(s)
- Raúl A Salazar-González
- Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY, 40202-1617, USA
| | - Xiaoyan Zhang
- Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY, 40202-1617, USA
- Department of Clinical Pharmacology, ADC Therapeutics, Murray Hill, NJ, USA
| | - Mark A Doll
- Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY, 40202-1617, USA
| | - Angeliki Lykoudi
- Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY, 40202-1617, USA
| | - David W Hein
- Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY, 40202-1617, USA.
| |
Collapse
|
|
38
|
A Novel Discovery: Holistic Efficacy at the Special Organ Level of Pungent Flavored Compounds from Pungent Traditional Chinese Medicine. Int J Mol Sci 2019; 20:ijms20030752. [PMID: 30754631 PMCID: PMC6387020 DOI: 10.3390/ijms20030752] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 12/25/2022] Open
Abstract
Pungent traditional Chinese medicines (TCMs) play a vital role in the clinical treatment of hepatobiliary disease, gastrointestinal diseases, cardiovascular diseases, diabetes, skin diseases and so on. Pungent TCMs have a vastness of pungent flavored (with pungent taste or smell) compounds. To elucidate the molecular mechanism of pungent flavored compounds in treating cardiovascular diseases (CVDs) and liver diseases, five pungent TCMs with the action of blood-activating and stasis-resolving (BASR) were selected. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between pungent flavored compounds and their holistic efficacy at the special organ level. First, we identified target proteins that are associated with pungent flavored compounds and found that these targets were functionally related to CVDs and liver diseases. Then, based on the phenotype that directly links human genes to the body parts they affect, we clustered target modules associated with pungent flavored compounds into liver and heart organs. We applied systems-based analysis to introduce a pungent flavored compound-target-pathway-organ network that clarifies mechanisms of pungent substances treating cardiovascular diseases and liver diseases by acting on the heart/liver organ. The systems pharmacology also suggests a novel systematic strategy for rational drug development from pungent TCMs in treating cardiovascular disease and associated liver diseases.
Collapse
|
|
39
|
Finlayson KA, Leusch FDL, van de Merwe JP. Primary green turtle (Chelonia mydas) skin fibroblasts as an in vitro model for assessing genotoxicity and oxidative stress. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2019; 207:13-18. [PMID: 30502692 DOI: 10.1016/j.aquatox.2018.11.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/26/2018] [Accepted: 11/26/2018] [Indexed: 06/09/2023]
Abstract
Little is known about the effects of contaminants that accumulate in sea turtles. When in vivo exposure studies have ethical and logistical barriers, as is the case with sea turtles, in vitro tools can provide important information on the effects of contaminants. Several in vitro studies have assessed cytotoxicity of contaminants to sea turtles cells, however to gain a more refined mechanistic understanding of the effects of contaminants, sub-lethal effects also require investigation. Considering the complex mixture of contaminants that sea turtles are potentially exposed to, high throughput testing methods are necessary so that a large number of contaminants (and mixtures) can be rapidly tested. This study examined oxidative stress (reactive oxygen species production) and genotoxicity (micronucleus formation) in primary green turtle skin fibroblasts in response to 16 organic and inorganic contaminants found in coastal environments. Significant induction of oxidative stress was found with Cu, Co, Cr, and Hg. Significant effects on genotoxicity were found with Cu, Co, Cr, Hg, Pb and metolachlor. Effect concentrations from the bioassays were used in a simple risk assessment of turtles worldwide using accumulation values from the literature to identify populations at risk. Cu, Co, Cr and Hg were identified as posing the biggest threat to sea turtles. This study demonstrated the validity of using primary turtle cell cultures in the assessment of risk associated with a large number of contaminants using a high-throughput toxicity testing format.
Collapse
Affiliation(s)
- Kimberly A Finlayson
- Australian Rivers Institute, School of Environment and Science, Griffith University, Gold Coast, Australia.
| | - Frederic D L Leusch
- Australian Rivers Institute, School of Environment and Science, Griffith University, Gold Coast, Australia
| | - Jason P van de Merwe
- Australian Rivers Institute, School of Environment and Science, Griffith University, Gold Coast, Australia
| |
Collapse
|
|
40
|
Zhang Q, Ji S, Chai L, Yang F, Zhao M, Liu W, Schüürmann G, Ji L. Metabolic Mechanism of Aryl Phosphorus Flame Retardants by Cytochromes P450: A Combined Experimental and Computational Study on Triphenyl Phosphate. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2018; 52:14411-14421. [PMID: 30421920 DOI: 10.1021/acs.est.8b03965] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Understanding metabolic mechanisms is critical and remains a difficult task in the risk assessment of emerging pollutants. Triphenyl phosphate (TPHP), a widely used aryl phosphorus flame retardant (aryl-PFR), has been frequently detected in the environment, and its major metabolite was considered as diphenyl phosphate (DPHP). However, knowledge of the mechanism for TPHP leading to DPHP and other metabolites is lacking. Our in vitro study shows that TPHP is metabolized into its diester metabolite DPHP and mono- and dihydroxylated metabolites by cytochromes P450 (CYP) in human liver microsomes, while CYP1A2 and CYP2E1 isoforms are mainly involved in such processes. Molecular docking gives the conformation for TPHP binding with the active species Compound I (an iron IV-oxo heme cation radical) in specific CYP isoforms, showing that the aromatic ring of TPHP is likely to undergo metabolism. Quantum chemical calculations have shown that the dominant reaction channel is the O-addition of Compound I onto the aromatic ring of TPHP, followed by a hydrogen-shuttle mechanism leading to ortho-hydroxy-TPHP as the main monohydroxylated metabolite; the subsequent H-abstraction-OH-rebound reaction acting on ortho-hydroxy-TPHP yields the meta- and ipso-position quinol intermediates, while the former of which can be metabolized into dihydroxy-TPHP by fast protonation, and the latter species needs to go through type-I ipso-substitution and fast protonation to be evolved into DPHP. We envision that the identified mechanisms may give inspiration for studying the metabolism of several other aryl-PFRs by CYP.
Collapse
Affiliation(s)
- Quan Zhang
- College of Environment , Zhejiang University of Technology , Hangzhou 310032 , China
| | - Shujing Ji
- College of Environmental and Resource Sciences , Zhejiang University , Hangzhou 310058 , China
| | - Lihong Chai
- College of Environmental and Resource Sciences , Zhejiang University , Hangzhou 310058 , China
| | - Fangxing Yang
- College of Environmental and Resource Sciences , Zhejiang University , Hangzhou 310058 , China
| | - Meirong Zhao
- College of Environment , Zhejiang University of Technology , Hangzhou 310032 , China
| | - Weiping Liu
- College of Environmental and Resource Sciences , Zhejiang University , Hangzhou 310058 , China
| | - Gerrit Schüürmann
- UFZ Department of Ecological Chemistry , Helmholtz Centre for Environmental Research , Permoserstrasse 15 , 04318 Leipzig , Germany
- Institute for Organic Chemistry , Technical University Bergakademie Freiberg , Leipziger Strasse 29 , 09596 Freiberg , Germany
| | - Li Ji
- College of Environmental and Resource Sciences , Zhejiang University , Hangzhou 310058 , China
| |
Collapse
|
|
41
|
Rendic SP, Guengerich FP. Development and Uses of Offline and Web-Searchable Metabolism Databases - The Case of Benzo[a]pyrene. Curr Drug Metab 2018; 19:3-46. [PMID: 29219051 DOI: 10.2174/1389200219666171207123939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 11/04/2017] [Accepted: 11/11/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND The present work describes development of offline and web-searchable metabolism databases for drugs, other chemicals, and physiological compounds using human and model species, prompted by the large amount of data published after year 1990. The intent was to provide a rapid and accurate approach to published data to be applied both in science and to assist therapy. METHODS Searches for the data were done using the Pub Med database, accessing the Medline database of references and abstracts. In addition, data presented at scientific conferences (e.g., ISSX conferences) are included covering the publishing period beginning with the year 1976. RESULTS Application of the data is illustrated by the properties of benzo[a]pyrene (B[a]P) and its metabolites. Analysis show higher activity of P450 1A1 for activation of the (-)- isomer of trans-B[a]P-7,8-diol, while P4501B1 exerts higher activity for the (+)- isomer. P450 1A2 showed equally low activity in the metabolic activation of both isomers. CONCLUSION The information collected in the databases is applicable in prediction of metabolic drug-drug and/or drug-chemical interactions in clinical and environmental studies. The data on the metabolism of searched compound (exemplified by benzo[a]pyrene and its metabolites) also indicate toxicological properties of the products of specific reactions. The offline and web-searchable databases had wide range of applications (e.g. computer assisted drug design and development, optimization of clinical therapy, toxicological applications) and adjustment in everyday life styles.
Collapse
Affiliation(s)
| | - Frederick P Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
| |
Collapse
|
|
42
|
Hahne JC, Valeri N. Non-Coding RNAs and Resistance to Anticancer Drugs in Gastrointestinal Tumors. Front Oncol 2018; 8:226. [PMID: 29967761 PMCID: PMC6015885 DOI: 10.3389/fonc.2018.00226] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs are important regulators of gene expression and transcription. It is well established that impaired non-coding RNA expression especially the one of long non-coding RNAs and microRNAs is involved in a number of pathological conditions including cancer. Non-coding RNAs are responsible for the development of resistance to anticancer treatments as they regulate drug resistance-related genes, affect intracellular drug concentrations, induce alternative signaling pathways, alter drug efficiency via blocking cell cycle regulation, and DNA damage response. Furthermore, they can prevent therapeutic-induced cell death and promote epithelial-mesenchymal transition (EMT) and elicit non-cell autonomous mechanisms of resistance. In this review, we summarize the role of non-coding RNAs for different mechanisms resulting in drug resistance (e.g., drug transport, drug metabolism, cell cycle regulation, regulation of apoptotic pathways, cancer stem cells, and EMT) in the context of gastrointestinal cancers.
Collapse
Affiliation(s)
- Jens C. Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
- Department of Medicine, The Royal Marsden NHS Trust, London, United Kingdom
| |
Collapse
|
|
43
|
Darband SG, Kaviani M, Yousefi B, Sadighparvar S, Pakdel FG, Attari JA, Mohebbi I, Naderi S, Majidinia M. Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. J Cell Physiol 2018; 233:6544-6560. [PMID: 29663361 DOI: 10.1002/jcp.26595] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/12/2018] [Indexed: 02/06/2023]
Abstract
Recently, an intense attention has been paid to the application of natural compounds as a novel therapeutic strategy for cancer treatment. Quercetin, a natural flavonol present in many commonly consumed food items, is widely demonstrated to exert inhibitory effects on cancer progression through various mechanisms. Since there is a strong association with diets containing abundant vegetables, fruits, and grains, and significant decline in the risk of colon cancer, accumulation studies have focused on the anticancer potential of quercetin in colorectal cancer. Cell cycle arrest, increase in apoptosis, antioxidant replication, modulation of estrogen receptors, regulation of signaling pathways, inhibition of and metastasis and angiogenesis are among various mechanisms underlying the chemo-preventive effects of quercetin in colorectal cancer. This review covers various therapeutic interactions of Quercetin as to how targets cellular involved in cancer treatment.
Collapse
Affiliation(s)
- Saber G Darband
- Danesh Pey Hadi Co., Health Technology, Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Sadighparvar
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Firouz G Pakdel
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Javad A Attari
- Department of Neurosurgery, Urmia University of Medical Sciences, Urmia, Iran
| | - Iraj Mohebbi
- Social Determinants of Health Center, Occupational Medicine Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Somayeh Naderi
- Danesh Pey Hadi Co., Health Technology, Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
44
|
Bradshaw PR, Wilson ID, Gill RU, Butler PJ, Dilworth C, Athersuch TJ. Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems. Sci Rep 2018; 8:2405. [PMID: 29402925 PMCID: PMC5799297 DOI: 10.1038/s41598-018-20464-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 12/18/2017] [Indexed: 12/18/2022] Open
Abstract
The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5–10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human in vivo metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human in vivo amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human in vivo hydrolytic metabolism of the aromatic amide compounds tested.
Collapse
Affiliation(s)
- Peter R Bradshaw
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ, UK
| | - Ian D Wilson
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ, UK
| | | | - Philip J Butler
- Cyprotex, Alderley Park, Nether Alderley, Cheshire, SK10 4TG, UK
| | - Clive Dilworth
- Cyprotex, Alderley Park, Nether Alderley, Cheshire, SK10 4TG, UK
| | - Toby J Athersuch
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ, UK. .,MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
| |
Collapse
|
|
45
|
Canova C, Richiardi L, Merletti F, Pentenero M, Gervasio C, Tanturri G, Garzino-Demo P, Pecorari G, Talamini R, Barzan L, Sulfaro S, Franchini G, Muzzolini C, Bordin S, Pugliese GN, Macrì E, Simonato L. Alcohol, Tobacco and Genetic Susceptibility in Relation to Cancers of the Upper Aerodigestive Tract in Northern Italy. TUMORI JOURNAL 2018; 96:1-10. [DOI: 10.1177/030089161009600101] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Each year in Italy there are approximately 14,000 new cases and 7,000 deaths from cancer of the upper aerodigestive tract, which includes malignant tumors originating from the oral cavity, pharynx, larynx and esophagus. Established etiological factors include tobacco consumption and heavy alcohol drinking. The study of single nucleotide polymorphisms in upper aerodigestive tract cancer etiology may help to identify high-risk subgroups and to better understand the pathways leading to the development of these cancers. Methods Italian results on about 500 cases and 500 controls from a large case-control study (ARCAGE) conducted in 10 European countries are presented with the major objectives of updating results on the effects of alcohol and tobacco consumptions in northern Italy, investigating the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke, and evaluating possible interactions of these single nucleotide polymorphisms with these carcinogens. Results The present study confirmed the importance of tobacco smoking and alcohol drinking as the main risk factors for upper aerodigestive tract cancers, indicating that about 68% of cancers among populations in northern Italy can be attributed to the combination of these risk factors. Significant associations between metabolizing phase I genes (CYP1A1 and CYP2A6), phase II genes (GSTA2) and upper aerodigestive tract cancers were found. A polymorphism of ADH1C has been associated with an increased risk of upper aerodigestive tract cancers, suggesting that the less rapid alcohol metabolizers are more susceptible to upper aerodigestive tract cancer risk. Conclusions Our results suggest that the ADH1C allele modifies the carcinogenic dose response for alcohol in the upper aerodigestive tract, giving rise to a gene-environment interaction. The role of genes as possible modifiers of life-style risks seems the most reliable.
Collapse
Affiliation(s)
- Cristina Canova
- Department of Environmental Medicine and Public Health, University of Padua, Padua
| | | | - Franco Merletti
- Unit of Cancer Epidemiology, CeRMS and University of Turin, Turin
| | | | | | | | | | | | - Renato Talamini
- Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, Aviano
| | - Luigi Barzan
- Head and Neck Unit, Pordenone General Hospital, Pordenone
| | | | - Giovanni Franchini
- Radiation Oncology Division, Centro di Riferimento Oncologico, IRCCS, Aviano
| | - Chiara Muzzolini
- Department of Environmental Medicine and Public Health, University of Padua, Padua
| | - Sandro Bordin
- Head and Neck Unit, SS Giovanni e Paolo Venice Hospital, Venice
| | | | - Ettore Macrì
- Department of Pathology, S. Martino Hospital, Belluno, Italy
| | - Lorenzo Simonato
- Department of Environmental Medicine and Public Health, University of Padua, Padua
| |
Collapse
|
|
46
|
Samuels ER, Sevrioukova I. Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities. Mol Pharm 2017; 15:279-288. [PMID: 29232137 DOI: 10.1021/acs.molpharmaceut.7b00957] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Structure-function relationships of nine rationally designed ritonavir-like compounds were investigated to better understand the ligand binding and inhibitory mechanism in human drug-metabolizing cytochrome P450 3A4 (CYP3A4). The analogs had a similar backbone and pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and terminal groups, respectively. N-Isopropyl, N-cyclopentyl, or N-phenyl were the R1-side group substituents alone (compounds 5a-c) or in combination with phenyl or indole at the R2 position (8a-c and 8d-f subseries, respectively). Our experimental and structural data indicate that (i) for all analogs, a decrease in the dissociation constant (Ks) coincides with a decrease in IC50, but no relation with other derived parameters is observed; (ii) an increase in the R1 volume, hydrophobicity, and aromaticity markedly lowers Ks and IC50, whereas the addition of aromatic R2 has a more pronounced positive effect on the inhibitory potency than the binding strength; (iii) the ligands' association mode is strongly influenced by the mutually dependent R1-R2 interplay, but the R1-mediated interactions are dominant and define the overall conformation in the active site; (iv) formation of a strong H-bond with Ser119 is a prerequisite for potent CYP3A4 inhibition; and (v) the strongest inhibitor in the series, the R1-phenyl/R2-indole containing 8f (Ks and IC50 of 0.08 and 0.43 μM, respectively), is still less potent than ritonavir, even under conditions that prevent the mechanism based inactivation of CYP3A4. Crystallographic data were essential for better understanding and interpretation of the experimental results, and suggested how the inhibitor design could be further optimized.
Collapse
Affiliation(s)
- Eric R Samuels
- Departments of Pharmaceutical Sciences and ‡Molecular Biology and Biochemistry, University of California , Irvine, California 92697-3900, United States
| | - Irina Sevrioukova
- Departments of Pharmaceutical Sciences and ‡Molecular Biology and Biochemistry, University of California , Irvine, California 92697-3900, United States
| |
Collapse
|
|
47
|
Rampal G, Thind TS, Arora R, Vig AP, Arora S. Synergistic antimutagenic effect of isothiocyanates against varied mutagens. Food Chem Toxicol 2017; 109:879-887. [DOI: 10.1016/j.fct.2017.05.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 05/05/2017] [Accepted: 05/09/2017] [Indexed: 10/19/2022]
|
|
48
|
Wang L, Ren G, Li J, Zhu L, Niu F, Yan M, Li J, Yuan D, Jin T. Genetic polymorphism analysis of cytochrome P4502E1 (CYP2E1) in a Chinese Tibetan population. Medicine (Baltimore) 2017; 96:e8855. [PMID: 29381998 PMCID: PMC5708997 DOI: 10.1097/md.0000000000008855] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Cytochrome P4502E1 (CYP2E1) gene genetic polymorphisms vary markedly in frequency among different ethnic and racial groups.We studied the genotype distributions and allele frequencies of 3 CYP2E1 polymorphisms: CYP2E11A, CYP2E17A, and CYP2E17C by polymerase chain reaction technique in a sample of 100 healthy subjects representing Tibetan population.The frequencies of CYP2E11A, 7A, and 7C alleles were 0.705, 0.125, and 0.170, respectively. Compared with other populations, we found that the allele frequencies of the variants -352A>G (rs2070672) and -333A>T (rs2070673) in this Tibetan population have significant differences compared with European-American, African-American, Japanese, Korean, and other different geographic areas in Chinese Han population. Furthermore, the results of protein prediction revealed that the variant 6397G>A (rs61710826) could influence the protein structure and function.These findings in this study would be valuable for pharmacogenetics for drug therapy and drug discovery. However, further studies in larger samples are warranted to confirm our results.
Collapse
Affiliation(s)
- Li Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Guoxia Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine of Xi’an Jiaotong University, Xi’an
- Department of Intergrated Traditional Chinese and Western Medicine, Xi’an Chest Hospital, Xi’an
| | - Jingjie Li
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Linhao Zhu
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Fanglin Niu
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Mengdan Yan
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Jing Li
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Dongya Yuan
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| |
Collapse
|
|
49
|
Rudik AV, Dmitriev AV, Bezhentsev VM, Lagunin AA, Filimonov DA, Poroikov VV. Prediction of metabolites of epoxidation reaction in MetaTox. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2017; 28:833-842. [PMID: 29157013 DOI: 10.1080/1062936x.2017.1399165] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 10/27/2017] [Indexed: 06/07/2023]
Abstract
Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ).
Collapse
Affiliation(s)
- A V Rudik
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
| | - A V Dmitriev
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
| | - V M Bezhentsev
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
| | - A A Lagunin
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
- b Medico-biological Faculty , Pirogov Russian National Research Medical University , Moscow , Russia
| | - D A Filimonov
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
| | - V V Poroikov
- a Institute of Biomedical Chemistry (IBMC) , Moscow , Russia
| |
Collapse
|
|
50
|
Ginsberg G, Vulimiri SV, Lin YS, Kancherla J, Foos B, Sonawane B. A framework and case studies for evaluation of enzyme ontogeny in children's health risk evaluation. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2017; 80:569-593. [PMID: 28891786 PMCID: PMC8018602 DOI: 10.1080/15287394.2017.1369915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals.
Collapse
Affiliation(s)
- Gary Ginsberg
- Partnership in Pediatric and Environmental Health, Hartford, CT 06134, USA
| | - Suryanarayana V. Vulimiri
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
| | - Yu-Sheng Lin
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
| | - Jayaram Kancherla
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20740, USA
| | - Brenda Foos
- Office of Children’s Health Protection, U.S. Environmental Protection Agency, Washington, DC, USA
| | - Babasaheb Sonawane
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
- Current Address: 13204 Moran Drive, North Potomac, MD 20878
| |
Collapse
|