title: Q172H replacement overcomes effects on the metabolism of cyclophosphamide and efavirenz caused by CYP2B6 variant with Arg262.
abstract: There are a number of reports indicating that CYP2B6*6 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.
authors.affiliation: Division of Pharmacy, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. ariyoshi@faculty.chiba-u.jp
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ariyoshi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ohara
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kaneko
authors.forename: Sakino
authors.initials: S
authors.lastname: Afuso
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Itsuko
authors.initials: I
authors.lastname: Ishii
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Mitsukazu
authors.initials: M
authors.lastname: Kitada
mesh_terms: D000480:Alkynes; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D048588:Benzoxazines / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism*; D010599:Pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz