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|Title:||Direct toxicity effects of sulfo-conjugated troglitazone on human hepatocytes|
In vitro cell toxicity
|Citation:||Saha, S., New, L.S., Ho, H.K., Chui, W.K., Chan, E.C.Y. (2010-06). Direct toxicity effects of sulfo-conjugated troglitazone on human hepatocytes. Toxicology Letters 195 (2-3) : 135-141. ScholarBank@NUS Repository. https://doi.org/10.1016/j.toxlet.2010.03.010|
|Abstract:||Troglitazone (TGZ), an orally active hypoglycemic agent, was found to be associated with severe drug-induced liver failure and was withdrawn from the market in 2000. Although the exact mechanism is not clear, it has been postulated that the formation of its major sulfo-conjugated metabolite (TGZS) plays an important role in its toxicity. TGZS inhibits bile salt export pump (BSEP) that causes accumulation of bile salts in liver. High concentration of bile salts causes cell death and mitochondrial dysfunction via detergent properties. One question arises whether TGZS has direct toxicity effect on human liver cells in addition to BSEP inhibition. In this study, both TGZ and chemically synthesized TGZS were incubated with normal human hepatocytes (THLE-2 cells) for measuring their cytotoxicity in vitro using the MTT assay. Glutathione (GSH) and protein carbonyl (PC) assays were further performed to measure the oxidative stress generated by these two compounds during incubation with THLE-2 cells. The results from this study indicated that TGZS (EC50=21.74±5.38μM) was more toxic than TGZ (EC50=41.12±4.3μM) in THLE-2 cells. The GSH and PC data further confirmed that TGZS produced greater oxidative stress in THLE-2 cells as compared to TGZ. In conclusion, our study demonstrated for the first time that TGZS has direct toxicity effect on human liver cells and may be partially responsible for the hepatotoxicity of TGZ. © 2010 Elsevier Ireland Ltd.|
|Source Title:||Toxicology Letters|
|Appears in Collections:||Staff Publications|
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