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Vol. 28, Issue 3, 354-359, March 2000
Toxicology Program, University of New Mexico, College of Pharmacy,
Albuquerque, New Mexico (M.R.W.); Department of Biochemistry, Mount
Sinai School of Medicine, New York, New York (J.M.L.); The Scripps
Research Institute, Department of Molecular and Experimental Medicine,
La Jolla, California (E.F.J.); and The La Jolla Institute
for Experimental Medicine, La Jolla, California (J.L.R.)
Tolbutamide is a sulfonylurea-type oral hypoglycemic agent whose
action is terminated by hydroxylation of the tolylsulfonyl methyl
moiety catalyzed by cytochrome P-450 (CYP) enzymes of the human
CYP2C subfamily. Although most studies have
implicated CYP2C9 as the exclusive catalyst of hepatic tolbutamide
hydroxylation in humans, there is evidence that other CYP2C enzymes
(e.g., CYP2C19) may also participate. To that end, we used an
immunochemical approach to assess the role of individual CYP2Cs in
microsomal tolbutamide metabolism. Polyclonal antibodies were raised to
CYP2C9 purified from human liver, and were then back-adsorbed against
recombinant CYP2C19 coupled to a solid-phase support. Western blotting
revealed that the absorbed anti-human CYP2C9 preparation reacted with
only recombinant CYP2C9 and the corresponding native protein in hepatic microsomes, and no longer recognized CYP2C19 and CYP2C8. Monospecific anti-CYP2C9 not only retained the ability to inhibit CYP2C9-catalyzed reactions, as evidenced by its marked (90%) inhibition of diclofenac 4'-hydroxylation by purified CYP2C9 and by human liver microsomes, but
also exhibited metabolic specificity, as indicated by its negligible
(<15%) inhibitory effect on S-mephenytoin
4'-hydroxylation by purified CYP2C19 or hepatic microsomes containing
CYP2C19. Monospecific anti-CYP2C9 was also found to inhibit rates of
tolbutamide hydroxylation by 93 ± 4 and 78 ± 6% in
CYP2C19-deficient and CYP2C19-containing human liver microsomes,
respectively. Taken together, our results indicate that both CYP2C9 and
CYP2C19 are involved in tolbutamide hydroxylation by human liver
microsomes, and that CYP2C19 underlies at least 14 to 22% of
tolbutamide metabolism. Although expression of CYP2C19 in human liver
is less than that of CYP2C9, it may play an important role in
tolbutamide disposition in subjects expressing either high levels of
CYP2C19 or a catalytically deficient CYP2C9 enzyme.
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