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Vol. 28, Issue 10, 1192-1197, October 2000
University of Pittsburgh Medical Center, Department of Pathology
(V.E.K., S.C.S.) and School of Pharmacy (V.R., R.V.), Pittsburgh,
Pennsylvania; Veterans Administration Medical Center, White River
Junction, Vermont (J.F.S.); Departments of Biochemistry and
Pharmacology/Toxicology, Dartmouth Medical School, Hanover, New
Hampshire (J.F.S.); and Worldwide Preclinical Safety (V.E.K., Y.H.W.)
and Department of Pharmacokinetics, Dynamics and Metabolism (E.K.,
V.G., K.R., M.S.), Parke-Davis Pharmaceutical Research
Co., Ann Arbor, Michigan
In primary human and porcine hepatocyte cultures, we investigated
the relationship between metabolism and cytotoxicity of troglitazone.
Treatment of human hepatocytes for 2 h with 10, 20, 25, 35, and 50 µM troglitazone in protein-free medium resulted in
concentration-dependent decreases in total protein synthesis. Decreases
at 10 and 20 µM were reversible by 24 h, however protein synthesis did not recover at concentrations 
25 µM. Troglitazone at
50 µM caused cellular death. In porcine hepatocytes, 100 µM troglitazone was lethal, whereas at 50 µM, protein synthesis
completely recovered by 24 h. Recovery in protein synthesis was
associated with metabolism of parent drug, whereas toxicity correlated
(r2 = 0.82) with accumulation of
unmetabolized troglitazone. By 1 h, in human hepatocytes,
troglitazone was metabolized to similar amounts of sulfate and quinone
metabolites with little glucuronide detected. In contrast, porcine
hepatocytes metabolized troglitazone to the similar amounts of
glucuronide and the quinone metabolites with little sulfate detected.
Exposure of human hepatocytes to a combination of 10 µM troglitazone
and 10 µM 2,4-dichloro-4-nitrophenol resulted in a 70% decrease in
protein synthesis, associated with 90% inhibition in the formation of
troglitazone sulfate, a 4-fold increase in unmetabolized troglitazone,
and no effect on formation of the quinone metabolite. Treatment with a
combination of acetaminophen or phenobarbital with 20 µM troglitazone
resulted in sustained decrease in protein synthesis associated with
inhibition of sulfation and accumulation of troglitazone. These results
suggest that inhibition of troglitazone sulfation may result in
increased hepatotoxicity due to exposure to parent drug, or increased
metabolism by alternate pathways.
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