Functional characterization of 20 allelic variants of CYP1A2.

ABSTRACT

Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7-ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2*4, CYP1A2*6, CYP1A2*8, CYP1A2*15, CYP1A2*16, and CYP1A2*21 were inactive toward both substrates. CYP1A2*11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2*14 and CYP1A2*20 exhibited increased activity compared to the wild-type enzyme, CYP1A2*1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies.