Enhancement of hepatocellular genotoxicity of several mutagens from amino acid pyrolysates and broiled foods following ethanol pretreatment.
The effect of subchronic ethanol ingestion on the genotoxicity and metabolism of the mutagens 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,5-b]indole (Trp-P-2), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4- dimethylimidazo[4,5-f]quinoline (MeIQ) was evaluated in primary cultures of rat hepatocytes. Male Sprague-Dawley rats were pair-fed, for 8 days, liquid diets containing either ethanol (8%, v/v) or an isocaloric sucrose solution. Ethanol pretreatment significantly (P less than 0.05, Student's t test) enhanced the level of DNA repair stimulated by Glu-P-1, Glu-P-2, IQ and MeIQ. Statistically significant increases in DNA-repair activity ranged from 1.9-fold for IQ to 3.4-fold for Glu-P-2. Following a 16-hr exposure, the concentration of parent mutagen in the culture medium decreased by 75-98%. Neither the rate of mutagen metabolism in hepatocyte cultures nor the extent of mutagenic activation in microsome preparations was appreciably affected by ethanol pretreatment. The results suggest that ethanol pretreatment enhances the genotoxicity of Glu-P-1, Glu-P-2, IQ and MeIQ by inducing non-microsomal activation processes.
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D006358:Hot Temperature; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D007211:Indoles / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D009152:Mutagenicity Tests; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains
D007093:Imidazoles; D007211:Indoles; D009153:Mutagens; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System