title: CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs.
abstract: CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A4*16 (T185S) and CYP3A4*18 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V(max)/K(m)) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K(m) with or without decreased V(max) values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K(m) values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V(max) values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug.
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. maekawa@nihs.go.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Harakawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Fumika
authors.initials: F
authors.lastname: Aohara
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Noriko
authors.initials: N
authors.lastname: Katori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tohkin
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Takuro
authors.initials: T
authors.lastname: Niwa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000483:Alleles; D000818:Animals; D000069059:Atorvastatin; D055162:Biocatalysis; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D002220:Carbamazepine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D000077143:Docetaxel; D005202:Asia, Eastern; D006538:Heptanoic Acids / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008874:Midazolam / Q000378:metabolism; D008958:Models, Molecular; D017239:Paclitaxel / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism; D018411:Spodoptera; D013379:Substrate Specificity; D043823:Taxoids / Q000378:metabolism; D016593:Terfenadine / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D002220:Carbamazepine; D000077146:Irinotecan; D016593:Terfenadine; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D008874:Midazolam; D002166:Camptothecin