Abstract

The azo dye carcinogen, N,N-dimethyl-4-aminoazobenzene (DAB), is metabolized initially by N-demethylation and 4'-hydroxylation. The metabolites appear in the bile principally as sulfates and glucuronides, and to a lesser extent as glutathione conjugates. Pretreatment with 3-methylcholanthrene (MC) or phenobarbital (PB) accelerates biliary excretion of metabolites. The responses are different for each inducing agent. PB induces N-demethylation and 4'-hydroxylation whereas MC induces N-demethylation but inhibits 4'-hydroxylation. These effects are evident in the in vitro metabolism of DAB and in vivo through analysis of biliary metabolites. MC induction accelerates N-demethylation of both the tertiary amine, 4'-OH-DAB, and the secondary amine, N-methyl-4-amino-4'-hydroxyazobenzene (4'-OH-MAB), whereas PB induction accelerates N-demethylation of 4'-OH-MAB but not of 4'-OH-DAB. A further distinction between the responses to MC and to PB is seen in the relative lack of effect of SKF 525-A on MC-induced metabolism and biliary excretion of DAB, whereas PB-induced and noninduced metabolism is markedly inhibited. Previous observations indicated a depressed N-demethylation and biliary excretion of DAB after glutathione depletion. These studies lead to the conclusion that N-demethylation is the major rate-determining factor for biliary excretion. 4'-Hydroxylation, although a prominent pathway, appears to be less critical to rates of biliary excretion.