Paradoxical effect of Sudan III on the in vivo and in vitro genotoxicity elicited by 7,12-dimethylbenz(a)anthracene.
Effect of the induction of drug metabolizing enzymes by Sudan III on the in vivo and in vitro genotoxicity elicited by 7,12-dimethyl-benz(a)anthracene (DMBA) was investigated. A significant suppression of DMBA-induced micronucleated reticulocytes was observed in C57BL/6 mice treated with Sudan III intraperitoneally for 3 or 5 days before injection of the DMBA. However, the preincubation of DMBA with hepatic microsomes from Sudan III-treated rats caused a marked increase in the in vitro mutagenicity in the Ames assay, paradoxically. Sudan III was found to induce CYP 1A1, 7-ethoxycoumarin O-deethylase activity as well as both UDP-glucuronyl transferase and glutathione S-transferase activities. The increase of mutagenicity of DMBA observed in the Ames assay using hepatic microsomes from Sudan III-treated rats was inhibited by the addition of uridine 5'-diphosphoglucuronic acid or reduced glutathione with cytosol. Mutagenic metabolites of DMBA formed by CYP1A1 appeared to be effectively detoxified by these phase II enzymes. The results of this study suggest that Sudan III-induced prevention of in vivo mutagenesis is due to the induction of both CYP 1A1 and detoxifying phase II enzymes. The induced CYP1A1 may accelerate formation of active metabolic intermediates, but phase II enzymes are also induced and detoxify these intermediates to inactive metabolites. This would reduce residence time of the carcinogen in the body and the time of exposure to active metabolites for target organs.
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001391:Azo Compounds / Q000494:pharmacology*; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005978:Glutathione / Q000494:pharmacology; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015162:Micronucleus Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D014535:Uridine Diphosphate Glucuronic Acid / Q000494:pharmacology
D016587:Antimutagenic Agents; D001391:Azo Compounds; D002273:Carcinogens; D009153:Mutagens; D014535:Uridine Diphosphate Glucuronic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; D005978:Glutathione; C033006:sudan III