The hepatic metabolism of two carcinogenic dimethylbenz[c]acridines in control and induced rats: the distribution and the mutagenicity of metabolites.
The major and minor metabolites of the potent polycyclic aza-aromatic carcinogens 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine, and the stereochemistry of the dihydrodiol metabolites have been previously described. The metabolite distributions produced in incubations of the aza-aromatic compounds with liver microsomes from phenobarbital- and 3-methylcholanthrene-pretreated and untreated rats, and the mutagenicity in the Ames test are described in this paper. The major metabolites of each were the alcohols produced by oxidation of the methyl group on the 8,9,10,11-ring for control and phenobarbital-induced preparations, while with 3-methylcholanthrene-induced preparations both the 7- and 9- (or 10-) monoalcohols were formed. Total monofunctionalized dihydrodiol metabolites, the 5,6- and 3,4-isomers for 7,9-dimethylbenz[c]acridine, and the 3,4-, 5,6- and 8,9-isomers for 7,10-dimethylbenz[c]acridine, constituted approximately 10% of total metabolites. As well, the K-region arene oxide was formed in substantial amounts with both compounds, accompanied in the case of 7,10-dimethylbenz[c]acridine with some 8,9-oxide. When incubations were carried out in the presence of the epoxide hydrase inhibitor 3,3,3-trichloropropane-1,2-oxide, dihydrodiol formation was almost completely inhibited and relative amounts of both phenols and oxides increased. Secondary metabolites were also formed to approximately 10% of the total products. The mutagenicity of synthetic alcohols and isolated purified metabolites was determined in the Salmonella mammalian microsome plate assay (Ames test) with strain TA100. Limited amounts of metabolites isolated precluded extensive testing, but high mutagenicities were noted for all 3,4-dihydrodiol derivatives isolated. These exceeded those of the parent aza-aromatic hydrocarbons. Alcohols were also active but less so than the parent compounds. The activation of these two dimethylbenz[c]acridines to mutagens appears to be through bay-region diolepoxides following patterns seen in other aza-aromatic compounds and the polycyclic aromatic hydrocarbons.
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Department of Pharmacy, University of Sydney, NSW, Australia.
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D000166:Acridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014018:Tissue Distribution; D014239:Trichloroepoxypropane
D000166:Acridines; D002273:Carcinogens; D009153:Mutagens; C010123:7,10-dimethylbenz(c)acridine; D014239:Trichloroepoxypropane; C031753:7,9-dimethylbenz(c)acridine; D004851:Epoxide Hydrolases