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Research ArticleArticle

Decreased Susceptibility of the Cytochrome P450 2B6 Variant K262R to Inhibition by Several Clinically Important Drugs

Jyothi C. Talakad, Santosh Kumar and James R. Halpert
Drug Metabolism and Disposition March 2009, 37 (3) 644-650; DOI: https://doi.org/10.1124/dmd.108.023655
Jyothi C. Talakad
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Santosh Kumar
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James R. Halpert
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Abstract

Cytochrome P450 (P450) 2B6 metabolizes a number of clinically relevant drugs and is one of the most highly polymorphic human P450 enzymes, with the Lys262→Arg substitution being especially common in several genetic variants. Therefore, K262R (2B6*4) was created in the CYP2B6dH background (N-terminal-modified and C-terminal His-tagged) and expressed in Escherichia coli. The recombinant CYP2B6dH and K262R were purified and studied to investigate the effect of the Lys262→Arg substitution with six of the most potent drug inhibitors of CYP2B6, namely, clopidogrel, clotrimazole, itraconazole, raloxifene, sertraline, and ticlopidine. K262R showed a >3-fold increase in the Ki values with clopidogrel, itraconazole, and raloxifene and ∼6-fold increase in Ki with sertraline compared with CYP2B6dH. Likewise, K262R showed 2-, 4-, and >20-fold higher Ks values than CYP2B6dH with clopidogrel, sertraline, and itraconazole, respectively. In contrast, when tested with several known type II inhibitors of CYP2B enzymes, K262R showed a 10-fold lower IC50 with 4-(phenyl)pyridine and ∼2-fold lower IC50 with 4-(4-nitrobenzyl)pyridine or 1-(4-phenyl)benzylimidazole than CYP2B6dH. Subsequent analysis predicted possible in vivo drug-drug interactions between the CYP2B6 substrate efavirenz and drug inhibitors clopidogrel, clotrimazole, itraconazole, sertraline, and ticlopidine. Furthermore, Q172H/K262R (2B6*6), which is the most common genetic variant of CYP2B6 harboring K262R, was created in CYP2B6dH, expressed, purified, and characterized for inhibition. Q172H/K262R showed a >6-fold increase in Ki with sertraline and clopidogrel compared with CYP2B6dH. The results suggest that individuals, especially homozygotes, with the 2B6*4 or 2B6*6 allele might be less susceptible to drug interactions resulting from P450 inhibition.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES03619, ES06676].

  • Parts of this work were previously presented as follows: Talakad JC, Sun L, Kumar S, and Halpert JR (2008) Characterization of the P450 2B6 genetic variant K262R for temperature stability and drug binding. Experimental Biology-2008; 2008 Apr 2–9; San Diego, CA. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD.

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

  • doi:10.1124/dmd.108.023655.

  • ABBREVIATIONS: P450, cytochrome P450; DDI, drug-drug interaction; 7-MFC, 7-methoxy-4-(trifluoromethyl)coumarin; CYMAL-5, 5-cyclohexylpentyl-β-d-maltoside; CSM, conserved sequence motif.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri.

    • Received July 30, 2008.
    • Accepted December 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (3)
Drug Metabolism and Disposition
Vol. 37, Issue 3
1 Mar 2009
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Research ArticleArticle

Decreased Susceptibility of the Cytochrome P450 2B6 Variant K262R to Inhibition by Several Clinically Important Drugs

Jyothi C. Talakad, Santosh Kumar and James R. Halpert
Drug Metabolism and Disposition March 1, 2009, 37 (3) 644-650; DOI: https://doi.org/10.1124/dmd.108.023655

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Research ArticleArticle

Decreased Susceptibility of the Cytochrome P450 2B6 Variant K262R to Inhibition by Several Clinically Important Drugs

Jyothi C. Talakad, Santosh Kumar and James R. Halpert
Drug Metabolism and Disposition March 1, 2009, 37 (3) 644-650; DOI: https://doi.org/10.1124/dmd.108.023655
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