DNA adduct levels of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in tissues of cynomolgus monkeys after single or multiple dosing.

Abstract

DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), a heterocyclic amine derived from cooked meat, were measured by the 32P-postlabeling method in tissues of cynomolgus monkeys given PhIP. Monkeys received either a single dose of PhIP (20 mg/kg orally) or nine daily doses of PhIP (20 mg/kg orally, days 1-5 and 8-11) and tissue samples were obtained 24 h after the last dose. Over 28 different tissues were examined for PhIP-DNA adducts. Adducts were detected in all tissues examined except the fat and bone marrow. After a single dose, adduct levels (mean value/10(7) nucleotides, n = 2 monkeys) were highest in the liver (2.1), followed by the lung (1.7), gall bladder (1.7) and pancreas (0.9). Low adduct levels were detected in the brain and aorta (0.06 and 0.02 respectively). Following multiple doses of PhIP, adduct levels (mean value/10(7) nucleotides +/- SE, n = 3 monkeys) were highest in the heart (5.7 +/- 2.0) followed by the liver (3.8 +/- 0.8), submandibular gland (2.7 +/- 1.8) and pancreas (2.2 +/- 0.5). Comparison of the adduct levels after a single dose with those found after multiple doses indicates that accumulation of PhIP-DNA adducts occurred in certain tissues. Adduct levels in liver, pancreas, kidney, small intestine and colon increased about 1.5- to 2.4-fold. PhIP-DNA adduct levels in submandibular gland and brain increased 4- to 5-fold. Adduct levels in heart increased 10-fold and levels in the aorta increased 31-fold. Adducts in white blood cell DNA increased with daily dosing for 9 days. No apparent changes in adduct levels were seen in the lung, stomach, bladder, muscle and spleen. The wide distribution of PhIP-DNA adducts and their presence in white blood cells suggests that there is transport of reactive metabolites from the liver to extrahepatic tissues. The relatively high adduct levels in the gall bladder in comparison with the liver suggests biliary excretion and possible reabsorption of reactive metabolites. The presence of DNA adducts in tissues implicates PhIP as a potential carcinogen in non-human primates. The possibility that PhIP-DNA adducts in tissues such as the heart and aorta may have toxicological consequences is discussed.