Induction of hepatic microsomal cytochrome P-448-mediated oxidases by 3,3′-Dichlorobenzidine in the rat

Abstract

Intraperitoneal administratioin of the hepatocarcinogen 3,3′-dichlorobenzidine (4,4′-diamino, 3,3′-dichlorobiphenyl) to adult male rats caused the induction of hepatic microsomal ethoxycoumarin O-deethylase and p-nitrophenetole O-deethylase activities comparable in magnitudes to those induced by 3-methylcholanthrene; neither anilin hydroxylase nor aminopyrine N-demethylase activity was affected by the pretreatment. The induction was not accompanied by a significant increase in content of hepatic microsomal cytochrome P-450; however, a shift in the absorption maxium of the reduced + CO spectrum of the cytochrome to 448 nm and an increase in the ratio of the 455 nm : 430 nm peaks of the reduced + ethylisocyanide spectrum of the hemoprotein was affected. Arylhydrocarbon hydroxylase activitity was stimulated 5-fold by dichlorobenzidine pretreatment in comparison with a 12-fold stimulation following 3-methylcholanthrene pretreatment. However, enzymatically mediated covalent binding of benzo[ a]pyrene to microsomal protein was greater in microsomes from dichlorobenzidine-pretreated rats than in those from methylcholanthrene-pretreated rats. All of the dichlorobenzidine-induced enzymic activities were inhibited by α-naphthoflavone but not by SKF-525A. Hepatic microsomes from dichlorobenzidine than those from untreated animalsl both sets of microsomes elicited the Type II spectral change on combination with the compound, albeit with different binding affinities and capacities. The results show that dichlorobenzidine, although only a dihalogenated biphenyl derivative, is a potent inducer of cytochrome P-448.