Q172H replacement overcomes effects on the metabolism of cyclophosphamide and efavirenz caused by CYP2B6 variant with Arg262

Noritaka Ariyoshi, Miyuki Ohara, Mayumi Kaneko, Sakino Afuso, Takuya Kumamoto, Hiroyoshi Nakamura, Itsuko Ishii, Tsutomu Ishikawa, Mitsukazu Kitada

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2045-2048
Number of pages4
JournalDrug Metabolism and Disposition
Volume39
Issue number11
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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