Induction and inhibition of the metabolism and biliary excretion of the azo dye carcinogen, N,N-dimethyl-4-aminoazobenzene (DAB), in the rat.
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.
D000818:Animals; D001646:Bile / Q000378:metabolism*; D003640:Dealkylation; D004789:Enzyme Activation / Q000187:drug effects; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D004124:p-Dimethylaminoazobenzene / Q000378:metabolism*
D008748:Methylcholanthrene; D004124:p-Dimethylaminoazobenzene; D011335:Proadifen; D006899:Mixed Function Oxygenases; D010634:Phenobarbital