Identification and functional characterization of new potentially defective alleles of human CYP2C19


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Abstract

CYP2C19 is a clinically important enzyme responsible for the metabolism of a number of therapeutic drugs, such as S-mephenytoin, omeprazole, diazepam, proguanil, propranolol and certain antidepressants. Genetic polymorphisms in this enzyme result in poor metabolizers of these drugs. There are racial differences in the incidence of the poor metabolizer trait, which represents 13–23% of Asians but only 3–5% of Caucasians. In this study, single nucleotide polymorphisms (SNPs) in CYP2C19 were identified by direct sequencing of genomic DNA from 92 individuals from three different racial groups of varied ethnic background, including Caucasians, Asians and blacks. Several new alleles were identified containing the coding changes Arg144His (CYP2C19*9), Pro227Leu (CYP2C19*10), Arg150His (CYP2C19*11), stop491Cys (CYP2C19*12), Arg410Cys (CYP2C19*13), Leu17Pro (CYP2C19*14) and Ile19Leu (CYP2C19*15). When expressed in a bacterial cDNA expression system, CYP2C19*9 exhibited a modest decrease in the Vmax for 4′-hydroxylation of S-mephenytoin, and no alteration in its affinity for reductase. CYP2C19*10 exhibited a dramatically higher Km and lower Vmax for mephenytoin. CYP2C19*12 was unstable and expressed poorly in a bacterial cDNA expression system. Clinical studies will be required to confirm whether this allele is defective in vivo. CYP2C19*9, CYP2C19*10 and CYP2C19*12 all occurred in African-Americans, or individuals of African descent, and represent new potentially defective alleles of CYP2C19 which are predicted to alter risk of these populations to clinically important drugs.

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