Alcoholdehydrogenase as an activating enzyme for N-nitrosodiethanolamine (NDELA): In vitro activation of NDELA to a potent mutagen in Salmonella typhimurium

Abstract

N-Nitrosodiethanolamine (NDELA), a potent carcinogen, has not so far been found to be mutagenic in a wide range of test systems. In particular, mutagenicity testing in Salmonella typhimurium with rat liver S-9 mix or microsomal fraction used for activation has failed to indicate mutagenicity. However, when incubated with alcohol dehydrogenase (ADH) in the presence of NAD, NDELA is converted to a potent mutagen. A possible mechanism of activation comprises the generation of an aldehyde as a primary metabolite formed by NAD/ADH and its subsequent rearrangement into cyclic intermediates. The latter might either be further metabolized or spontaneously decompose into various alkylating agents and glycolaldehyde. Standard test conditions used for the Ames test will not favor the detection of mutagens to be activated by NAD/ADH because they require the presence of NADPH, whereas ADH needs NAD to become an activating enzyme, as shown for NDELA.