Abstract

Halogenated ethenes are oxidatively metabolized by cytochrome P-450 to intermediates which inactivate cytochrome P-450 by destroying heme and to epoxides which may react with cellular macromolecules or decompose to other products. To determine the relative capabilities of fluoroethenes to inactivate cytochrome P-450 and undergo metabolism, fluoride release, cytochrome P-450 loss, and heme loss due to the metabolism of trifluorochloroethene (TFCE), chlorodifluoroethene (CDE), difluoroethene (DFE), and trifluoroethene (TFE) were compared in rat hepatic microsomes. Fluoride release, in order of decreasing amounts of fluoride released, followed the order: CDE greater than TFCE much greater than TFE greater than DFE. In contrast, in order of each compound's decreasing effectiveness to destroy both cytochrome P-450 and heme, the following sequence was obtained: TFE greater than CDE greater than TFCE greater than DFE. In phenobarbital-induced hepatic microsomes, TFE inactivated up to 67% of the cytochrome P-450, whereas DFE inactivated only up to 17%. The results of this study indicate that chloro substituents enhance defluorination of the ethenes, and that cytochrome P-450 inactivation by the fluoroethenes is highly dependent on the degree and nature of the halogen substituents.