Cellular distribution of cytochrome P-450 loss in rats of different ages treated with alkyl halides

Abstract

Challenge of male rats with a single dose of the alkyl halides, 1,2-dibromo-3-chloropropane (DBCP), ethylene dibromide (EDB), carbon tetrachloride (CCl 4), and epichlorohydrin (EPI), resulted in significant decreases in cytochrome P-450 in microsomes isolated from liver, kidney, testis, lung, and small intestinal mucosa 48 hr after treatment. Treatment with CCl 4, but not DBCP, EDB, or EPI, was characterized by rapid loss of cytochrome P-450, detectable within 4 hr. Evidence of lipid peroxidation was found only in hepatic microsomes from rats treated with CCl 4, but not in hepatic or extrahepatic microsomes from rats treated with other compounds. In liver tissue, treatment with DBCP and CCl 4 resulted in a decrease in cytochrome P-450 in both rough and smooth microsomal fractions and nuclei, but not in mitochondrial fractions. Mixed-function oxidase (MFO) activities in hepatic microsomes decreased in parallel with cytochrome P-450 content after treatment with DBCP and EDB. In microsomes and nuclei after treatment with CCl 4 and in nuclei after treatment with DBCP, however, the response of the MFO depended on the substrate tested. Microsomal cytochrome P-450, which is susceptible to proteolytic cleavage, and microsomal and nuclear cytochrome P-450, which increased with maturation and decreased with aging of the rat, appeared to be the most responsive of the forms of cytochrome P-450 to alkyl halide treatment. These results suggest that treatment with alkyl halides may preferentially affect specific isozymes of cytochrome P-450.