J Pharmacol Exp Ther. 1997 Nov;283(2):434-42.  

Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of
omeprazole by human liver microsomes: effects of contents of these two forms in
individual human samples.

Yamazaki H, Inoue K, Shaw PM, Checovich WJ, Guengerich FP, Shimada T.

Osaka Prefectural Institute of Public Health, 3-69 Nakamichi 1-chome,
Higashinari-ku, Osaka 537, Japan.

Omeprazole 5-hydroxylation and sulfoxidation activities were determined in liver
microsomes of different humans whose levels of individual forms of cytochrome
P450 (P450 or CYP) varied. Correlation coefficients between omeprazole
5-hydroxylation activities (when determined at a substrate concentration of 10
microM) and S-mephenytoin 4'-hydroxylation and testosterone 6beta-hydroxylation
activities were found to be 0.64 and 0.67, respectively, in liver microsomes of
84 human samples examined. Omeprazole sulfoxidation activities in these human
samples were correlated with testosterone 6beta-hydroxylation activities (r = 0.
86). Omeprazole 5-hydroxylation by liver microsomes of a human sample that
contained relatively high levels of CYP3A4 and low levels of CYP2C19 were
inhibited very significantly by ketoconazole and anti-CYP3A4 antibodies,
although a human sample having high in CYP2C19 and low in CYP3A4 was found to be
sensitive toward fluvoxamine and anti-CYP2C9 antibodies. Sulfaphenazole (at 100
microM) did not affect the omeprazole 5-hydroxylation and sulfoxidation
catalyzed by human liver microsomes. Both recombinant human CYP2C19 and CYP3A4
enzymes had activities for omeprazole 5-hydroxylation, with low Km and high Vmax
values for the former enzyme and high Km and low Vmax values for the CYP3A4.
These results suggest that contributions of CYP2C19 and CYP3A4 in the omeprazole
5-hydroxylation depend upon the ratio of these two P450 levels in human liver
microsomes. Omeprazole 5-hydroxylation activities of different human samples
were found to be related to predicted values calculated from the kinetic
parameters of recombinant enzymes and the levels of liver microsomal CYP2C19 and
CYP3A4 enzymes. Finally, when recombinant human CYP2C19 and CYP3A4 were mixed at
levels found in different human samples, relatively similar profiles of
omeprazole oxidation by the recombinant and microsomal enzyme systems were
determined by analysis of high-performance liquid chromatography. These results
suggest that both CYP2C19 and CYP3A4 are involved in the 5-oxidation of
omeprazole (at a substrate concentration of 10 microM) in human liver microsomes
and that contributions of these P450 enzymes depend on the compositions of
CYP2C19 and CYP3A4 in liver.

PMID: 9353355 [PubMed - indexed for MEDLINE]