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Vol. 27, Issue 11, 1260-1266, November 1999
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa,
Japan (H.Y., A.S., M.S., M.N., T.Y.); Daiichi Pure Chemicals, Ibaraki,
Japan (N.S.); and Department of Biochemistry and Center in Molecular
Toxicology, Vanderbilt University School of Medicine, Nashville,
Tennessee (F.P.G.)
Troglitazone, a new oral antidiabetic drug, is reported to be
mostly metabolized to its conjugates and not to be oxidized by
cytochrome P-450 (P-450) enzymes. Of fourteen cDNA-expressed human
P-450 enzymes examined, CYP1A1, CYP2C8, CYP2C19, and CYP3A4 were active
in catalyzing formation of a quinone-type metabolite at a concentration
of 10 µM troglitazone, whereas CYP3A4 had the highest catalytic
activity at 100 µM substrate. In human liver microsomes, rates of the
quinone-type metabolite formation (at 100 µM) were correlated well
with rates of testosterone 6
-hydroxylation (r = 0.98), but those at 10 µM troglitazone were not correlated with any
of several marker activities of P-450 enzymes. Quercetin efficiently
inhibited quinone-type metabolite formation (at 10 µM troglitazone)
in human samples that contained relatively high levels of CYP2C,
whereas ketoconazole affected these activities in liver microsomes in
which CYP3A4 levels were relatively high. Anti-CYP2C antibodies
strongly inhibited quinone-type metabolite formation (at 10 µM
troglitazone) in CYP2C-rich human liver microsomes (by ~85%); the
intensity of this effect depended on the human samples and their P-450
status. The results suggest that in human liver both CYP2C8 and CYP3A4
have major roles in quinone-type metabolite formation and that the
hepatic contents of these two P-450 forms determine which P-450 enzymes
play major roles in individual humans. CYP3A4 may be expected to play a
role in formation of quinone-type metabolite from troglitazone even at
a low concentration in humans.
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