Functional characterization of eight human CYP1A2 variants: the role of cytochrome b(5)
| Autor: | Bernardo Brito Palma, Michel Kranendonk, Phillipe Urban, José Rueff, Marta Silva e Sousa |
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| Přispěvatelé: | Dept Genet, Fac Med Sci, Univ Nova Lisboa, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), NIH [CA089392, CA77598, DA021237, 5T32MH0 14677-33, AA015572], Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Université de Toulouse (UT), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
[SDV]Life Sciences [q-bio]
CYP1A2 Genome-wide association study 0302 clinical medicine ETHNIC-DIFFERENCES Polymorphism (computer science) General Pharmacology Toxicology and Pharmaceutics GENETIC POLYMORPHISMS Clozapine DEFICIENT C-OXIDATION Genetics (clinical) Genetics 0303 health sciences Principal Component Analysis Phenacetin Analgesics Non-Narcotic METABOLIC PROFILE 030220 oncology & carcinogenesis Inactivation Metabolic Molecular Medicine Oxidation-Reduction pharmacokinetics FMO3 GENE Antipsychotic Agents cytochrome P450 Biology Catalysis 03 medical and health sciences Cytochrome P-450 CYP1A2 FLAVIN-CONTAINING MONOOXYGENASE-3 Cytochrome b5 Humans GENOME-WIDE ASSOCIATION Mode of action Molecular Biology 030304 developmental biology HAPLOTYPE RECONSTRUCTION pharmacogenomics Polymorphism Genetic Cytochrome P450 NICOTINE DEPENDENCE Kinetics cytochrome b(5) Cytochromes b5 Mutation biology.protein CIGARETTE-SMOKING polymorphisms Pharmacogenetics Drug metabolism |
| Zdroj: | Pharmacogenetics and Genomics Pharmacogenetics and Genomics, Lippincott, Williams & Wilkins, 2013, 23 (2), pp.41-68. ⟨10.1097/FPC.0b013e32835c2ddf⟩ Pharmacogenetics and Genomics, 2013, 23 (2), pp.41-68. ⟨10.1097/FPC.0b013e32835c2ddf⟩ |
| ISSN: | 1744-6872 |
| DOI: | 10.1097/FPC.0b013e32835c2ddf⟩ |
| Popis: | Background Interindividual variability in cytochrome P450 (CYP)-mediated xenobiotic metabolism is extensive. CYP metabolism requires two electrons, which can be donated by NADPH cytochrome P450 oxidoreductase (CYPOR) and/or cytochrome b5 (b5). Although substantial number of studies have reported on the function and effect of b5 in CYP-mediated catalysis, its mode of action is still not fully understood. Objective The aim of this work was to examine the effect of b5 on the activities of eight natural-occurring variants of human CYP1A2, namely, T83M, S212C, S298R, G299S, I314V, I386F, C406Y, and R456H. Materials and methods An approach, as used in our former study was applied, coexpressing these polymorphic CYP1A2 variants separately with CYPOR and b(5) in the bacterial cell model BTC-CYP. For each variant, 16 different activity parameters were measured, using eight different substrates. This heterogeneous data set was merged with the one of our former study (i.e. without b(5)) and a multivariate analysis was carried out. Results This analysis indicated that b(5) seems to have the ability to affect CYP1A2 variants to behave more like the wild-type variant. This was especially the case for variant I386F, for which the presence of b(5) was crucial to show activity. Variants T83M and C406Y showed considerably different activity-profiles when in the presence of b5. Furthermore, our data seem to implicate CYP1A2 residue G299 in its interaction with CYPOR and/or b5. Conclusion Results indicate the ability of b(5) to affect CYP1A2 variants to behave more like the wild-type variant, attenuating detrimental effects of structural mutations of these variants, seemingly through extensive allosteric effects. Pharmacogenetics and Genomics 23:41-52 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2013, 23:41-52 |
| Databáze: | OpenAIRE |
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