In-vivo activation of N-nitrosodiethanolamine and other n-nitroso-2-hydroxyalkylamines by alcohol dehydrogenase and sulfotransferase.

Alcohol dehydrogenase (ADH) activates N-nitrosodiethanolamine (NDELA) to a potent mutagen in the Ames mammalian microsome mutagenicity assay. In vivo, NDELA, its metabolite N-nitroso-2-hydroxymorpholine (NHMOR) and other 2-hydroxylated N-nitrosoalkylamines induce single-strand breaks in rat liver after a single oral application. After competitive inhibition of ADH by pretreatment with ethanol, induction of single-strand breaks by NDELA and N-nitroso(2-hydroxyethyl)ethylamine (NHEEA) was completely suppressed, whereas breaks induced by NHMOR were only partially reduced. Ethanol also influences cytochrome P450-dependent monooxygenases. To investigate whether the observed effect depends on inhibition of ADH and/or of monooxygenases, rats were pretreated with the ADH inhibitor 3-butylthiolane-1-oxide; a considerable reduction in the single-strand-break-inducing potential of NDELA was seen. Moreover, DNA damage induced by NDELA, NHMOR and other hydroxylated N-nitroso compounds is strongly reduced by pretreatment with the sulfotransferase inhibitor, 2,6-dichloro-4-nitrophenol (DCNP). DCNP pretreatment completely suppressed the induction of single-strand breaks by NDELA, whereas the number induced by NHEEA was only partially reduced. Our data suggest that ADH and sulfotransferase are enzymes responsible for the in-vivo activation of N-nitroso-2-hydroxyalkylamines.