Halomethane hepatotoxicity: induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver microsomes under low oxygen partial pressures.

Halomethane-induced lipid peroxidation and inactivation of cytochrome P-450 were studied in liver microsomes from phenobarbital-pretreated rats in the presence of NADPH at steady-state O2 partial pressures (PO2). As indicated by the formation of thiobarbituric acid-reactive material and the stimulation of O2 uptake, significant lipid peroxidation was induced by those halomethanes containing more than two Cl, Br, or I atoms. Lipid peroxidation decisively depended on the PO2 present, showing distinct maxima at PO2 between 1 and 10 mm Hg. Those halomethanes inducing lipid peroxidation also led to inactivation of microsomal cytochrome P-450, as indicated by a loss of cytochrome P-450 detectable as ferrous CO complex and an equimolar loss of microsomal heme. Under anaerobic conditions inactivation of cytochrome P-450 presumably resulted solely from an attack of halomethane radicals on its heme moiety. Under aerobic conditions lipid peroxidation made an additional contribution to the inactivation of cytochrome P-450. These results suggest that the reductive activation to free radicals, catalyzed by cytochrome P-450, and thus the induction of lipid peroxidation at low but physiological PO2 are characteristic not only of CCl4 but also of other polyhalogenated methanes, especially CBrCl3, CBr4, CHI3, CHBr3, and CHBr2Cl.