N-Nitrosodiethanolamine is activated in the rat to an ultimate genotoxic metabolite by sulfotransferase

Abstract

Inhibition of sulfotransferase by 2,6-dichloro-4-nitrophenol (DCNP) has been found to completely abolish the genotoxic potential of N-nitrosodiethanolamine (NDELA) in rat liver as indicated by induction of DNA single strand breaks. The DNA strand breaking potential of N-nitroso-2-hydroxymorpholine (NHMOR), a metabolite of NDELA formed by alcohol dehydrogenase-mediated oxidation, was also almost quantitatively abolished. In contrast to these beta-hydroxylated nitrosamines, the effectiveness of N-nitrosodiethylamine (NDEA) remained unaffected by DCNP with respect to its DNA damaging potential. N-Nitrosoethylethanolamine (NEELA) was the most potent genotoxic agent of this series of nitrosamines and its strand breaking activity was only partially inhibited by DCNP. A new activation mechanism for NDELA is proposed: NDELA is transformed at first by alcohol dehydrogenase into the cyclic hemiacetal NHMOR. This cyclic beta-hydroxynitrosamine appears to be a substrate for sulfotransferase. The resulting sulfate conjugate is suggested to be the ultimate genotoxic electrophile. However, the results do not exclude the possiblity that NDELA itself undergoes sulfate conjugation.

Comparative tumorigenicity of N-nitroso-2-hydroxymorpholine, N-nitrosodiethanolamine and N-nitrosomorpholine in A/J mice and F344 rats

“…Sterzel and Eisenbrand have suggested that sulfation of NDELA may be an activation mechanism, since induction of single-strand breaks was abolished by a sulfotransferase inhibitor (28). NDELA sulfate could cause 2-hydroxyethylatio n of DNA according to the mechanism proposed by Michejda and coworkers (29).…”

Genotoxicity of glycidamide in comparison to (±)‐anti‐benzo[a]pyrene‐7,8‐dihydrodiol‐9,10‐epoxide and α‐acetoxy‐N‐nitroso‐diethanolamine in human blood and in mammalian V79‐cells

“…After metabolic activation it has been shown to induce DNA-SSB in vitro in the human lymphoblastoid cell line Namalva [15]. After oral NDELA-application to rats, DNA strand break formation was observed in the liver [15,25,26]. Moreover, using P450-2E1-transfected V79 cells, NDELA was found to be cytotoxic and mutagenic, reflecting the involvement of P450-2E1 in its bioactivation [27].…”

Probing the Mechanism of the Carcinogenic Activation of N-Nitrosodiethanolamine with Deuterium Isotope Effects: In Vivo Induction of DNA Single-Strand Breaks and Related in Vitro Assays

“…Airoldi () observed a correlation between the the extent of β-oxidation of NDELA, as measured by production of metabolites NHMOR and NHEG, and its carcinogenicity in four different animal species. Both NDELA and NHMOR are effective producers of DNA SSB in rat liver DNA ( − ). The DNA SSB produced by NDELA or NHMOR are either blocked or significantly modulated by inhibitors of ADH, P450, sulfotransferase, and probably other enzymes ( − ).…”

“…Both NDELA and NHMOR are effective producers of DNA SSB in rat liver DNA ( − ). The DNA SSB produced by NDELA or NHMOR are either blocked or significantly modulated by inhibitors of ADH, P450, sulfotransferase, and probably other enzymes ( − ). While the inhibitors used in these experiments are likely to have effected more than a single enzyme system, the experiments were indicative of and supportive of the β-oxidation path.…”