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Vol. 283, Issue 2, 434-442, 1997
Osaka Prefectural Institute of Public Health, 3-69 Nakamichi
1-chome, Higashinari-ku, Osaka 537, Japan (H.Y., K.I., T.S.);
PanVera
Corporation, 545 Sciences Drive, Madison, Wisconsin (P.M.S., W.J.C.);
and
Department of Biochemistry and Center in Molecular Toxicology,
Vanderbilt University School of Medicine, Nashville, Tennessee (F.P.G.)
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 µM) and S-mephenytoin 4
-hydroxylation and testosterone 6
-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 6-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 µM) 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 µM) in human liver microsomes and that contributions of these
P450 enzymes depend on the compositions of CYP2C19 and CYP3A4 in liver.
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