Metabolic activation of chemical carcinogens by hepatic preparations from streptozotocin-treated rats.
The effect of insulin-dependent diabetes on the hepatic microsomal activation of chemical carcinogens to mutagenic intermediates in the Ames test was investigated in rats pretreated with streptozotocin. In order to discern between the effects of streptozotocin itself and that of the resulting diabetes, groups of streptozotocin-treated rats received either nicotinamide simultaneously with the diabetogenic agent to prevent the onset of diabetes or daily treatment with insulin in order to antagonise the effects of diabetes. The activation of two nitrosamines, nitrosopiperidine and nitrosopyrrolidine was markedly increased following treatment of the animals with streptozotocin, the effect being preventable by nicotinamide and effectively antagonised by insulin. A similar increase in mutagenic response was also seen when Glu-P-1, a carcinogen generated during the cooking of proteinaceous food, was employed as the mutagen. In contrast, the diabetic rats were less efficient than control animals in activating the aromatic amine 2-aminofluorene to mutagenic intermediates. Concomitant administration of nicotinamide with streptozotocin prevented the decrease in mutagenicity, and daily treatment of diabetic rats with insulin partially restored mutagenic response to control levels. Streptozotocin-induced diabetes had no effect on the mutagenicity of 4-aminobiphenyl and the two polycyclic aromatic hydrocarbons, benzo(a)pyrene and 3-methylcholanthrene. The present findings clearly illustrate that diabetes modulates the metabolic activation of carcinogenic chemicals, the effect being dependent on the nature of the carcinogen.
Flatt
P R
PR
Biochemistry Department, University of Surrey, UK.
Bass
S L
SL
Ayrton
A D
AD
Trinick
J
J
Ioannides
C
C
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008748:Methylcholanthrene / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D009536:Niacinamide / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D002273:Carcinogens; D007093:Imidazoles; D007328:Insulin; D009153:Mutagens; D009602:Nitrosamines; D009536:Niacinamide; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole