N-nitrosodimethylamine-derived O6-methylguanine in DNA of monkey gastrointestinal and urogenital organs and enhancement by ethanol

Abstract

N-nitrosodimethylamine (NDMA) is a human cancer initiator suspect. Ethanol, a cancer risk factor, may synergize with nitrosamines by suppressing 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,generating the promutagenic DNA lesion O6-methylguanine (O6-meG). Adult monkeys received 0.1 mg/kg NDMA by gavage, in some cases preceded by ethanol. Four hours after NDMA only, O6-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, amounts of O6-meG increased at least 2-fold in all tissues except liver. The largest effect was in esophagus (17-fold increase), followed by ovary, large intestine, urinary bladder, spleen and cerebellum (9- to 13-fold increases), and uterus, cerebrum and brain stem (7- to 8-fold increases). Alkylguanine alkyltransferase activities varied over a 30-fold range and were highest in liver and stomach. Thus primate tissues, especially those of the gastrointestinal and urogenital organs, are sensitive targets for DNA adduct damage due to NDMA, and ethanol co-exposure leads to striking increases in adducts. Our data support epidemiology implicating nitrosamines in causation of cancers of stomach and other organs, and alcohol as enhancing internal exposure to nitrosamines.