RT Journal Article SR Electronic T1 The Role of Conjugation in Hepatotoxicity of Troglitazone in Human and Porcine Hepatocyte Cultures JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1192 OP 1197 VO 28 IS 10 A1 Vsevolod E. Kostrubsky A1 Jacqueline F. Sinclair A1 Vinod Ramachandran A1 Raman Venkataramanan A1 Yuan Hua Wen A1 Erick Kindt A1 Vladimir Galchev A1 Kelly Rose A1 Michael Sinz A1 Stephen C. Strom YR 2000 UL http://dmd.aspetjournals.org/content/28/10/1192.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics