Date of Graduation
1992
Document Type
Thesis
Abstract
Dichloroacetic acid (DCA) and chloroform (CHCl{dollar}\\sb3{dollar}) both are major by-products formed during chlorination of drinking water. The potential threat to public health, of these compounds, is of great concern. Male and female rats were gavaged with DCA (2.45 mmol/kg), and then received an i.p. injection of CHCl{dollar}\\sb3{dollar} (0.25 ml/kg). The activities of plasma liver enzymes and the contents of plasma bilirubin were markedly increased in DCA-pretreated rats compared to their saline-pretreated controls. The possible mechanisms of CHCl{dollar}\\sb3{dollar}-induced hepatotoxicity potentiated by DCA treatment were investigated. It was hypothesized that the bioactivation of CHCl{dollar}\\sb3{dollar} in rats was enhanced by DCA treatment. The in vitro CHCl{dollar}\\sb3{dollar} metabolism, including CO{dollar}\\sb2{dollar} production and covalent binding, was significantly increased after DCA treatment in both sexes. The metabolism of CHCl{dollar}\\sb3{dollar} was cytochrome P450-mediated and the reactive metabolites of CHCl{dollar}\\sb3{dollar} were formed by cytochrome P450-mediated oxidation as well as reduction. DCA treatment also increased the relative activity and the relative amount of P450IIE1, the P450 isozyme may be responsible for CHCl{dollar}\\sb3{dollar} metabolism, in both males and females. Since neither P450IIB1/2 nor P450IA1 was induced after DCA treatment, P450IIE1 likely accounted for the enhanced metabolism of CHCl{dollar}\\sb3{dollar} and the increased hepatotoxicity in DCA-treated male and female rats. DCA treatment changed the profile of hepatic mixed function oxidase as well as the content of hepatic glutathione differently in male and female rats, suggesting that CHCl{dollar}\\sb3{dollar} metabolism and/or the susceptibility of these rats to CHCl{dollar}\\sb3{dollar} toxicity may be affected differently after DCA treatment. Both the apparent K{dollar}\\sb{lcub}\\rm m{rcub}{dollar} for conversion of {dollar}\\sp{lcub}14{rcub}{dollar}CHCl{dollar}\\sb3{dollar} to {dollar}\\sp{lcub}14{rcub}{dollar}CO{dollar}\\sb2{dollar} and the apparent K{dollar}\\sb{lcub}\\rm m{rcub}{dollar} for protein binding were up to 5-fold higher in the males compared to the females, and the responses of these rats to SKF 525-A were significantly sex different, indicating that CHCl{dollar}\\sb3{dollar} metabolism may be sex-related and the different enzymes may involve CHCl{dollar}\\sb3{dollar} metabolism in male and female rats. Overall, these results support the hypothesis that enhanced biotransformation of CHCl{dollar}\\sb3{dollar} by DCA treatment is one of the mechanisms contributing to this potentiation.
Recommended Citation
Yang, Hui-Min, "Biotransformation as a mechanism of dichloroacetic acid potentiation of chloroform hepatotoxicity." (1992). Graduate Theses, Dissertations, and Problem Reports. 10071.
https://researchrepository.wvu.edu/etd/10071