Dose-dependent formation of preneoplastic foci and DNA adducts in rat Liver with 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)

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Abstract
Dose responses to two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), in induction of glutathione Stransferase placental form positive liver cell foci (GS-P+ foci) and DNA adduct formation in the liver were examined in male F344 rats. Beginning 2 weeks after a single diethylnitrosamine (DEN) injection (200 mg/kg, i.p.), rats received MeAαC or PhIP in the diet at various doses for 6 weeks. All rats were subjected to two-thirds partial hepatectomy (PH) 1 week after the test agents were added to the diet and were killed 8 weeks after DEN initiation. MeAαC (100, 200, 400 and 800 p.p.m.) significantly increased numbers and areas of GST-P+ foci over control levels in all dose groups with a clear dose–response. In contrast, PhIP (50, 100, 200 and 400 p.p.m.) only equivocally increased foci development in the highest dose group and rather was associated with decrease in the lower dose groups. DNA addud formation assessed by 32P-postlabeling demonstrated a dose-dependent increase with both chemicals, the levels being much higher with MeAαC. Thus, two highly mutagenic heterocyclic amines that are produced in broiled foodstuffs exerted different influence on GS-P+ foci development and DNA adduct formation; these findings are consistent with liver carcinogenicity in rats and/or mice.

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