The biotransformation and reactive metabolite formation of halogenated ethenes has been associated with the carcinogenic, hepatotoxic, and nephrotoxic potentials of many of these compounds. Exposure of individuals to the fluorinated forms of these compounds can occur from their use as monomers in industry, and from the generation of one (2-chloro-l,l-difluoroethene, CDE) as a reductive metabolite of halothane. Few studies have dealt with the oxidative metabolism and liver toxicity of the fluoro-substituted ethenes, even though evidence exists for their mutagenic and hepatotoxic properties. The long term objectives of this study, therefore, are to provide a greater understanding of the metabolism of the fluorinated ethenes, and the biochemical consequences of their metabolism. It is proposed to study these compounds because of new evidence that cytochrome P-450 metabolism of fluoroethenes is important. They 1) liberate large amounts of fluoride, 2) are potent inactivators of cytochrome P-450, 3) can covalently bind to microsomal protein, and 4) are susceptible in vitro and in vivo to strong stimulatory effects by certain anesthetics and halocarbons. CDE, trifluorochloroethene (TFCE), trifluoroethene (TFE), and difluoroethene (DFE), will be studied in hepatic microsomes, purified cytochrome P-450, and whole animals, to determine 1) their major metabolic pathways and abilities to undergo metabolism and activation, 2) the mechanisms by which anesthetics and related halocarbons stimulate their metabolism, 3) the roles of the cytochrome P-450 forms, (those induced by phenobarbital and ethanol [P-450alc]), in their metabolism, and 4) their abilities to induce hepatotoxic effects under different metabolizing conditions. The procedures to be used are haloethene metabolite identification techniques involving GC, HPLC, and ion-specific electrodes, and binding assays using radiolabeled substrates. Hepatotoxicities will be determined by release of serum enzymes following exposure of animals to fluoroethenes and anesthetics via inhalation.
