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Research ArticleArticle

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 and Mitsukazu Kitada
Drug Metabolism and Disposition November 2011, 39 (11) 2045-2048; DOI: https://doi.org/10.1124/dmd.111.039586
Noritaka Ariyoshi
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Miyuki Ohara
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Mayumi Kaneko
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Sakino Afuso
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Takuya Kumamoto
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Hiroyoshi Nakamura
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Itsuko Ishii
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Tsutomu Ishikawa
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Mitsukazu Kitada
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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.

Footnotes

  • This study was supported by The Nakatomi Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.039586.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    SNP
    single nucleotide polymorphism
    CPA
    cyclophosphamide
    EFV
    efavirenz
    POR
    NADPH-cytochrome P450 oxidoreductase
    HPLC
    high-performance liquid chromatography.

  • Received March 16, 2011.
  • Accepted August 5, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (11)
Drug Metabolism and Disposition
Vol. 39, Issue 11
1 Nov 2011
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Research ArticleArticle

UNIQUE EFFECTS OF Q172H ON CATALYTIC ACTIVITY OF CYP2B6

Noritaka Ariyoshi, Miyuki Ohara, Mayumi Kaneko, Sakino Afuso, Takuya Kumamoto, Hiroyoshi Nakamura, Itsuko Ishii, Tsutomu Ishikawa and Mitsukazu Kitada
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2045-2048; DOI: https://doi.org/10.1124/dmd.111.039586

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Research ArticleArticle

UNIQUE EFFECTS OF Q172H ON CATALYTIC ACTIVITY OF CYP2B6

Noritaka Ariyoshi, Miyuki Ohara, Mayumi Kaneko, Sakino Afuso, Takuya Kumamoto, Hiroyoshi Nakamura, Itsuko Ishii, Tsutomu Ishikawa and Mitsukazu Kitada
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2045-2048; DOI: https://doi.org/10.1124/dmd.111.039586
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