5-hydroxylation of omeprazole by human liver microsomal fractions from Chinese populations related to CYP2C19 gene dose and individual ethnicity.
It has been previously reported that omeprazole (OP) oxidation is mediated by CYP2C19 and CYP3A4 in human livers. In this study, we assessed their relative contributions with human liver microsomal fractions from Chinese populations that were genotyped by CYP2C19 and recruited from two ethnic groups, Han and Zhuang. The kinetics of 5-hydroxyomeprazole (5-OH-OP) formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equations for liver microsomes from CYP2C19 extensive (EMs) and poor metabolizers, respectively. At a low substrate concentration that may be encountered in vivo, the monoclonal antibody to CYP2C8/9/19 strongly inhibited 5-OH-OP formation in EM microsomes, whereas troleandomycin (TAO) eliminated most of the formation at a high substrate concentration. In poor metabolizer microsomes, either TAO or anti-CYP3A4 could alone abolish 5-OH-OP formation. Furthermore, there were differences between homozygous and heterozygous EMs in the percentage of inhibition by TAO and the antibodies. At the low substrate concentration, OP 5-hydroxyaltion was correlated well with S-mephenytoin 4'-hydroxylation and CYP2C19 contents in liver microsomes of 34 Chinese individuals. Moreover, in these individuals, obviously genetic and somewhat ethnic differences in OP 5-hydroxylation were observed between different CYP2C19 genotypes (wt/wt > wt/m1 > m1/m1) and between Han and Zhuang (Han > Zhuang), respectively. The results indicate that CYP2C19 is a high-affinity enzyme for OP 5-hydroxylation by liver microsomes from Chinese individuals and that its contribution is CYP2C19 gene dependent and ethnically related. Similar studies indicate that OP sulfoxidation is mediated mainly by CYP3A4 and independent of CYP2C19 genotype status.
Shu
Y
Y
Pharmacogenetics Research Institute, Hunan Medical University, Changsha, China. yans@itsa.ucsf.edu
Wang
L S
LS
Xu
Z H
ZH
He
N
N
Xiao
W M
WM
Wang
W
W
Huang
S L
SL
Zhou
H H
HH
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002681:China; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics*; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008617:Mephenytoin / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000378:metabolism*; D013379:Substrate Specificity; D014217:Troleandomycin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D065607:Cytochrome P-450 Enzyme Inhibitors; C040450:omeprazole sulfone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D008617:Mephenytoin