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Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C
김주환,임영란,한송희,한정수,천영진,윤철호,이창훈,김동학 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.12
CYP2D6 is responsible for the oxidativemetabolism of 20–25 % of clinical drugs and its geneticpolymorphisms can significantly influence the drugmetabolism. In this study, we analyzed the functionalactivities of four nonsynonymous single nucleotide polymorphismsfrom CYP2D6*52 allele, which were recentlyfound, and one found frequently in CYP2D6 alleles. Recombinant variant enzymes of E418K, S486T, andR296C were successfully expressed in Escherichia coli andpurified. However, a CYP holoenzyme spectrum of P34Svariant was not detected in E. coli whole cell level. Structural analysis indicated that P34S mutation seemed toperturb a highly conserved proline-rich N-terminus ofCYP2D6. Steady state kinetic analyses showed the significantreductions of enzymatic activities in E418K andR296C variants. In the case of bufuralol 1’-hydroxylation,a novel mutant, E418K, showed 32 % decrease in catalyticefficiency (kcat/Km) mainly due to the decrease of kcatvalue. R296C showed much greater reduction in the catalyticefficiency (9 % of wild-type) due to both of a decrease of kcat value and an increase of Km value. In the case ofdextromethorphan O-demethylation, E418K showed bothof a decrease of kcat value and an increase Km value toresult in *43 % reduction of catalytic efficiency. A highlydecreased catalytic efficiency (*6 % of wild-type) in themutant of R296C also was observed mainly due to thedramatic change of kcat value of dextromethorphanO-demethylation. These results suggested that individualscarrying these allelic variants are likely to have the alteredmetabolic abilities of many clinical drugs therefore, thesepolymorphisms of CYP2D6 should be much concerned forreliable drug treatment.
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