Various agricultural, industrial, and pharmaceutical agents contain 2,4-thiazolidinedione (TZD) rings. For example, a TZD ring is found in the insulin-sensitizing agents, troglitazone, rosiglitazone and pioglitazone, which have been or are used in the treatment of type II diabetes. Although the toxicology of the TZD ring has not been extensively investigated, troglitazone was removed from the market after it was associated with over 70 cases of hepatotoxicity that required transplants or resulted in deaths. There have also been reports of liver injuries in patients taking rosiglitazone and pioglitazone. The mechanism by which these drugs damage the liver is not known, although metabolism in the TZD ring may be a factor. Unfortunately, there are no reliable animal models to investigate this process. Recently, 3-(3,5-dichlorophenyl)-2,4- thiazolidinedione (DCPT) was found to reproducibly cause liver damage in rats. Since this compound also contains a TZD ring, it is conceivable the presence of this structural feature may be critical for the production of hepatotoxicity. Therefore, DCPT may be a useful model compound to investigate TZD ring-induced liver damage in a commonly used laboratory animal species. In analogy to the insulin-sensitizing agents, it is also conceivable that DCPT must undergo metabolism before liver damage will occur. The current proposal is designed to examine the hypothesis that biotransformation in the TZD ring contributes to the hepatotoxicity of DCPT in rats. This hypothesis will be tested through the following Specific Aims: (1) investigate the effect of structural modification on DCPT-induced liver damage in rats to determine if the TZD ring is essential for liver damage; (2) examine of the effect of metabolic enzyme activity modulation on DCPT-induced hepatotoxicity in rats to establish if metabolism in the TZD ring is required for hepatotoxicity; and (3) investigate the potential formation of reactive intermediates from DCPT in vitro, in an effort to elucidate the nature of any putative toxic metabolites that may be generated via biotransformation. The reproducible liver damage that DCPT causes in an animal model may provide a unique opportunity to investigate the potential participation of the TZD ring in liver damage. Since people are exposed to TZD ring-containing compounds, this work may form the basis for future studies about TZD ring-induced hepatotoxicity in humans.
