In-vitro analysis of the contribution of CYP2D6.35 to ultrarapid metabolism

From 10 to 30% of CYP2D6 ultra-rapid metabolizers of Caucasian origin harbo r alleles with duplicated or amplified functional CYP2D6 genes. Recently, t he CYP2D6*35 allele has been reported to be more frequent in ultra-rapid me tabolizing subjects than in extensive metabolizers, suggesting a possible r ole of this variant in CYP2D6 duplication-negative ultra-rapid metabolizing subjects. In this study, we examined the functional consequences of the Va l(11)Met, Arg(296)Cys and Ser(486)Thr amino acid substitutions associated w ith the CYP2D6*35 on the expression and catalytic activity of the variant e nzyme, heterologously expressed in yeast. Our results indicate that the fun ctional activity and level of expression of recombinant CYP2D6.35 are compa rable with those of the wild-type enzyme, thus precluding the hypothesis th at the high level of enzyme activity in CYP2D6 duplication-negative ultra-r apid metabolizing subjects is a consequence of the expression of a more cat alytically effective CYP2D6.35 enzyme. Pharmacogenetics 11:739-741 (C) 2001 Lippincott Williams & Wilkins.