N-NITROSODIMETHYLAMINE-DERIVED O-6-METHYLGUANINE IN DNA OF MONKEY GASTROINTESTINAL AND UROGENITAL ORGANS AND ENHANCEMENT BY ETHANOL

N-nitrosodimethylamine (NDMA) is a human cancer initiator suspect. Eth anol, a cancer risk factor, may synergize with nitrosamines by suppres sing hepatic clearance, to increase internal exposure. A limitation to these hypotheses is lack of activation of NDMA by many rodent tissues . However, systematic primate studies are lacking. Patas monkeys were utilized to investigate NDMA activation by primate tissues in vivo, ge nerating the promutagenic DNA lesion O-6-methylguanine (O-6-meG). Adul t monkeys received 0.1 mg/kg NDMA by gavage, in some cases preceded by ethanol. Four hours after NDMA only, O-6-meG was detected in DNA from all tissues. Levels were highest in gastric mucosa and liver and were only about 50% lower in DNA from white blood cells, esophagus, ovary, pancreas, urinary bladder and uterus. With ethanol co-exposure, amoun ts of O-6-meG increased at least 2-fold in all tissues except liver. T he largest effect was in esophagus (17-fold increase), followed by ova ry, large intestine, urinary bladder, spleen and cerebellum (9- to 13- fold increases), and uterus, cerebrum and brain stem (7- to 8-fold inc reases). Alkylguanine alkyltransferase activities varied over a 30-fol d range and were highest in liver and stomach. Thus primate tissues, e specially those of the gastrointestinal and urogenital organs, are sen sitive targets for DNA adduct damage due to NDMA, and ethanol co-expos ure leads to striking increases in adducts. Our data support epidemiol ogy implicating nitrosamines in causation of cancers of stomach and ot her organs, and alcohol as enhancing internal exposure to nitrosamines . (C) 1996 Wiley-Liss, Inc.