Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6 β -Hydroxylation.

Autor:	Kumondai M; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Gutiérrez Rico EM; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Hishinuma E; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Ueda A; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Saito S; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Saigusa D; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Tadaka S; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Kinoshita K; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Nakayoshi T; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Oda A; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Abe A; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Maekawa M; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Mano N; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Hirasawa N; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.)., Hiratsuka M; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (M.K., E.M.G.R., N.H., M.H.), Tohoku Medical Megabank Organization (E.H., S.S., D.S., S.T., K.K., M.H.), Advanced Research Center for Innovations in Next-Generation Medicine (E.H., A.U., N.H., M.H.), and Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences (A.A., M.M., N.M.), Tohoku University, Sendai, Japan; Faculty of Pharmacy, Meijo University, Nagoya, Japan (T.N., A.O.); and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., N.M., N.H., M.H.) masahiro.hiratsuka.a8@tohoku.ac.jp.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2021 Mar; Vol. 49 (3), pp. 212-220. Date of Electronic Publication: 2020 Dec 31.
DOI:	10.1124/dmd.120.000261
Abstrakt:	CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone). The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment. The kinetic parameters of midazolam and testosterone hydroxylation by wild-type CYP3A4 and 29 CYP3A4 variants ( K m , k cat , and catalytic efficiency) were determined, and the causes of their kinetic differences were evaluated by three-dimensional structural modeling. Our findings offer insight into the mechanism underlying interindividual differences in CYP3A4-dependent drug metabolism. Moreover, our results provide guidance for improving drug administration protocols by considering the information on CYP3A4 genetic polymorphisms. SIGNIFICANCE STATEMENT: CYP3A4 metabolizes more than 30% of clinically used drugs. Interindividual differences in drug efficacy and adverse-effect rates have been linked to ethnicity-specific differences in CYP3A4 gene variants in Asian populations, including Japanese individuals, indicating the presence of CYP3A4 polymorphisms resulting in the increased expression of loss-of-function variants. This study detected alterations in CYP3A4 activity due to amino acid substitutions by assessing the enzymatic activities of coding variants for two representative CYP3A4 substrates. Competing Interests: The authors declare no conflict of interest. (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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