Received for publication February 26, 2007.
Revised April 25, 2007.
Accepted for publication April 26, 2007.

COMPARATIVE METABOLIC CAPABILITIES AND INHIBITORY PROFILES OF CYP2D6.1, CYP2D6.10, AND CYP2D6.17

Abstract

Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null-alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains largely unexplained. Thus the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17 were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 as compared to CYP2D6.1, yielding 1.32?7.9% and 7.33?0.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which are lower, higher or comparable to CYP2D6.1. Considering the rather high frequencies of CYP2D6^*10 and CYP2D6^*17 alleles for Asians and African-Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.

Key words: CYP inhibition, CYP2D, enzyme inhibitors, enzyme kinetics, ethnic differences, human CYP enzymes, mass spectrometry, pharmacogenetics, polymorphisms, recombinant proteins

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