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Drug Metabolism & Disposition

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Functional characterization of 40 CYP3A4 variants by assessing midazolam 1′-hydroxylation and testosterone 6β-hydroxylation

Masaki Kumondai, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Daisuke Saigusa, Shu Tadaka, Kengo Kinoshita, Tomoki Nakayoshi, Akifumi Oda, Ai Abe, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition December 31, 2020, DMD-AR-2020-000261; DOI: https://doi.org/10.1124/dmd.120.000261
Masaki Kumondai
1Tohoku University, Japan
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Evelyn Marie Gutiérrez Rico
1Tohoku University, Japan
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Eiji Hishinuma
1Tohoku University, Japan
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Akiko Ueda
1Tohoku University, Japan
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Sakae Saito
1Tohoku University, Japan
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Daisuke Saigusa
1Tohoku University, Japan
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Shu Tadaka
1Tohoku University, Japan
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Kengo Kinoshita
1Tohoku University, Japan
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Tomoki Nakayoshi
2Meijo University, Japan
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Akifumi Oda
2Meijo University, Japan
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Ai Abe
1Tohoku University, Japan
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Masamitsu Maekawa
3Tohoku University Hospital, Japan
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Nariyasu Mano
3Tohoku University Hospital, Japan
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Noriyasu Hirasawa
1Tohoku University, Japan
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Masahiro Hiratsuka
4Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
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  • ORCID record for Masahiro Hiratsuka
  • For correspondence: masahiro.hiratsuka.a8@tohoku.ac.jp
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Abstract

Cytochrome P450 3A4 (CYP3A4) is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of the clinically used drugs. Therefore, inter-individual 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 4,776 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 (Km, kcat, 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 inter-individual 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 the clinically used drugs. Inter-individual differences in drug efficacy and adverse effect rates have been linked to ethnic-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.

  • CYP3A4
  • Cytochrome P450 (CYP)
  • drug metabolism
  • Genetic polymorphisms
  • pharmacogenetics/pharmacogenomics
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Functional characterization of 40 CYP3A4 variants

Masaki Kumondai, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Daisuke Saigusa, Shu Tadaka, Kengo Kinoshita, Tomoki Nakayoshi, Akifumi Oda, Ai Abe, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition December 31, 2020, DMD-AR-2020-000261; DOI: https://doi.org/10.1124/dmd.120.000261

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OtherArticle

Functional characterization of 40 CYP3A4 variants

Masaki Kumondai, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Daisuke Saigusa, Shu Tadaka, Kengo Kinoshita, Tomoki Nakayoshi, Akifumi Oda, Ai Abe, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition December 31, 2020, DMD-AR-2020-000261; DOI: https://doi.org/10.1124/dmd.120.000261
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