BROMOPROPYLATE - INDUCTION OF HEPATIC CYTOCHROMES P450 AND ABSENCE OFCOVALENT BINDING TO DNA IN MOUSE-LIVER

Oral administration of benzilic acid ester-based acaricide bromopropyl ate at daily doses of 3, 15, 100, and 300 mg/kg body wt to young adult male Tif:MAGf mice for 14 days caused slightly increased liver weight s in the high-dose group. A dose-dependent increase of the microsomal cytochrome P450 content was accompanied by elevated ethoxycoumarin O-d eethylase, ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylas e, and total testosterone hydroxylase activities. When compared with m ice treated in parallel with the model compounds for hepatic xenobioti c metabolizing enzyme induction, phenobarbitone, and 3-methylcholanthr ene, the enzyme activity changes observed with bromopropylate largely equalled those expressed in phenobarbitone-treated mice. Immunochemica l studies with monoclonal antibodies against rat liver cytochrome P450 isoenzymes of the gene families 1A, 2B, 3A, and 4A confirmed that bro mopropylate is a phenobarbitone-type inducer in the mouse liver. Titra tion of liver microsomal suspensions with bromopropylate yielded Type I substrate binding spectra. The specific amplitude was increased 1.5- fold when microsomes from bromopropylate-treated mice (300 mg/kg body wt) were used instead of control microsomes, indicating the induction of cytochromes P450 catalyzing the oxidative metabolism of the test co mpound. Single oral administration of 300 mg/kg body wt [C-14]- bromop ropylate to male mice, without or following pretreatment for 14 days w ith 300 mg/kg body wt unlabeled bromopropylate, gave no indication for DNA binding of the test compound in the liver. This excludes a genoto xic potential via covalent DNA modification The results suggest that, in analogy to phenobarbitone, bromopropylate acts as a tumor promotor rather than a tumor initiator in the mouse liver. (C) 1994 Academic Pr ess, Inc.