Inter-individual variation of cytochrome P4502J2 expression and catalytic activities in liver microsomes from Japanese and Caucasian populations

Abstract

The aim of this study was to investigate the inter-individual variations in cytochrome P4502J2 (CYP2J2) and its typical drug oxidation activities in human liver microsomes in both Japanese and Caucasian populations. CYP2J2 contents were determined immunochemically in liver microsomes from 20 Japanese and 29 Caucasian samples using recombinant CYP2J2 commercially available as a standard. Ebastine hydroxylation and astemizole O-demethylation activities were compared. The CYP2J2 genotype was determined by direct sequencing of liver genomic DNA. The mean expression levels of CYP2J2 determined immunochemically in liver microsomes from Japanese and Caucasian samples were 2.0 +/- 1.5 and 1.2 +/- 2.1 pmol CYP2J2 mg-1 protein (mean +/- standard deviation), respectively, accounting for 1.8 +/- 1.1% and 0.52 +/- 0.65% of the total hepatic P450 content (0.15 +/- 0.19 and 0.27 +/- 0.14 nmol P450 mg-1 protein, respectively). The individual variation of the two marker drug oxidation activities could not be fully accounted for by the CYP2J2 contents or currently known CYP2J2 genotypes. The amounts of CYP2J2 in liver microsomes with the CYP2J2*7 allele (-76G>T) were decreased to 39% compared with those of liver microsomes from other individuals. The results indicate that CYP2J2 accounts for approximately 1-2% of total P450 in human liver microsomes. The information about large inter-individual variation of the CYP2J2 suggests that this enzyme plays a significant role in the metabolism of xenobiotics and may be useful in in-silico simulations of drug disposition.