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First published on March 15, 2005; DOI: 10.1124/dmd.105.003749

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Received for publication January 20, 2005.
Revised March 9, 2005.
Accepted for publication March 11, 2005.

The Naturally Occuring P450 2B6 K262R Mutant of P450 2B6 Exhibits Alterations in Substrate Metabolism and Inactivation

Namandje N Bumpus 1, Chitra Sridar 1, Ute M Kent 1, Paul F. Hollenberg 2*

1 University of Michigan 2 University of Michigan School of Medicine

* Address correspondence to: E-mail: phollen{at}umich.edu

Abstract

The polymorphic human cytochrome P450 2B6 is primarily responsible for the metabolism of several clinically relevant drugs including bupropion, cyclophosphamide, propofol, and efavirenz. Although a number of single nucleotide polymorphisms (SNPs) have been found in the P450 2B6 gene, the influence of these variants on the metabolism of substrates and on the response to known inactivators of P450 2B6 have not been examined. We have compared the metabolism of different substrates of P450 2B6 (P450 {Delta}2B6) and the effects of mechanism-based inactivators with that observed with the polymorphic P450 {Delta}2B6 K262R in a reconstituted monooxygenase system (reconstituted system). Metabolism of bupropion by P450 {Delta}2B6 K262R resulted in increased production of hydroxybupropion compared to P450 {Delta}2B6. However, production of formaldehyde from the metabolism of benzphetamine by the P450 {Delta}2B6 K262R mutant was significantly less than that of the wild-type isozyme. P450 {Delta}2B6 K262R formed less benzphetamine metabolites compared to the wild-type. N,N',N"-triethylenethiophosphoramide (tTEPA) and bergamottin decreased the ability of both enzymes to hydroxylate bupropion and to O-deethylate 7-hydroxy-4-(trifluoromethyl) coumarin (7EFC). Incubation with 17-{alpha}-ethynylestradiol (17EE) decreased bupropion hydroxylation and 7EFC O-deethylation with the wild type enzyme but had no effect on the mutant. The kinetics for inactivation of the variant by tTEPA and bergamottin were determined using 7EFC. The KI values for inactivation of the variant were significantly greater than those determined for the wild-type enzyme. These data demonstrate a functional difference between P450 {Delta}2B6 and the allelic variant P450 {Delta}2B6 K262R.


Key words: CYP2B, cytochrome P450, drug-drug interactions, mechanism-based inhibition, polymorphisms


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