BIOCHEMICAL TOXICITY OF AGENTS INCREASING REACTIVE 02

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Reactive oxygen species have been shown to be important in a variety of toxic phenomena and may be the mediators of genotoxicity for a variety of carcinogens. The objective of the proposed research is to investigate the hypothesis that certain peroxisome-proliferating chemicals exert their liver carcinogenic effects by increasing intracellular levels of H2O2 giving rise to reactive oxygen species that damage DNA. The chemicals to be studied have been selected on the basis of their diverse chemical structure and the species specificity of their peroxisome-proliferating and hepatocarcinogenic effects. These chemicals include important environmental agents such as the industrial solvent, trichloroethylene, the phthalate plasticizers, and three hypolipidemic agents, two of which are used as human medications. The hepatocarcinogenic effects of these chemicals often occurs in only one rodent species in which induction of peroxisomes is seen. The described hypothetical mechanism will be tested by two experiments. First, the production and metabolism of H2O2 in suspensions of freshly isolated intact hepatocytes fromsusceptible and resistant species exposed to peroxisome-proliferating agents will be compared. Then, we will examine DNA isolated from livers of similarly exposed animals for oxidative damage known to be associated with mutation and cancer under other circumstances. Once this basic hypothesis has been tested, we proposed to expand the knowledge of the effect of these agents on intracellular H2O2 metabolism beyond their peroxisome proliferation. The in vivo and in vitro effects of these compounds on generation of H2O2 by isolated peroxisomes, mitochondria and endoplasmic reticulum will be investigated. A detailed analysis of the in vivo and in vitro effects on enzymes that decompose H2O2, catalase and glutathione peroxidase, will be performed. Also, effects on glutathione and glutathione-requiring enzymes will be assessed.