PHARMACOTOXICOLOGY OF TRICHLOROETHYLENE METABOLITES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project focuses on the kinetics, metabolism and human toxicology of dichloroacetate-DCA and chloral hydrate-CH, potentially harmful metabolites of trichloroethylene-TCE. Humans exhibit polymorphisms of MAAI that may possess different kinetic properties toward DCA. Human haplotype variability may influence DCA's kinetics and toxicology. These hypotheses will be tested by accomplishing the following Specific Aims: Specific Aim 1: Quantify the influence of DCA, at exposure levels ranging from environmental, ¿g/kg/d to clinical, mg/kg/d, on human liver MAAI and tyrosine catabolism. This aim tests the hypotheses that: there is a dose-dependent effect of DCA on human hepatocellular tyrosine metabolism in general and on the accumulation of potentially hepatotoxic tyrosine intermediates in particular; DCA inhibits hepatic MAAI expression in vivo in humans in a dose-dependent manner; and DCA, tyrosine and/or their metabolites form adducts with MAAI. Specific Aim 2: Establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism. This aim tests the postulates that MAAI haplotype determines, and thus can predict: dose-dependent DCA kinetics and biotransformation and DCA's effects on tyrosine metabolism. Specific Aim 3: Determine the in vivo kinetics and biotransformation of CH in healthy adults and the influence of CH and DCA on each other's metabolism. This specific aim will examine three postulates: CH is metabolized in adults to DCA; CH, via DCA formation, inhibits its own metabolism and that of tyrosine; and these effects are dependent upon exposure level but not upon gender.