Intestinal metabolism of nitrosamines. 1. Transport and metabolism of six nitrosamines in isolated perfused rat small intestinal segments

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Abstract
Possible relationships between structure and metabolism of nitrosamines have been investigated in the rat small intestine. Isolated segments of jejunum and ileum were perfused from the luminal side for 2 h with a Tyrode solution containing one of four symmetrical dialkylnitrosamines with 2–5 carbon atoms per side chain, all 14 C-labeled at the α position, or one of two unsymmetrical nitrosamines, N-nitroso-terf-butylmeth-ylamine and N-nitrosomethylbenzylamine, 14 C-labeled in the methyl group. Besides measurement of 14CO2 production and covalent binding of 14 C to intestinal tissue, the absorbed fluid (absorboate) as well as the perfusion medium and tissue hom-ogenates were analysed by h.p.l.c. for the presence of polar metabolites to assess the intestinal metabolism of nitrosamines. Neither N-nitrosodiethylamine nor the two unsymmetrical nitrosamines were metabolized to any significant extent. With increasing chain length of symmetrical dialkylnitrosamines small intestinal metabolism increased dramatically. At a concentration of 1 μM up to 60% and 30% of N-nitrosodipropyl-amine (NDPA) in jejunal and ileal segments, respectively, and >90% of N-nitrosodibutylamine (NDBA) and N-nitrosodi-pentylamine (NDAA) in both intestinal segments were metabolized during absorption. Metabolites were found also in perfusate and tissue homogenate but generally at lower percentages as compared with the absorbate. With increasing concentrations the percentage of metabolites decreased, the decrease being more pronounced in ileal as compared with jejunal segments. CO 2 production and covalent binding were negligible in ileal segments but amounted up to 5–8% and 0.1–0.4% of the dose in jejunal segments perfused with NDPA, NDBA or NDAA. With NDBA and NDAA no concentration-dependent decrease could be observed, the highest amounts of 14 CO 2 and bound 14 C being found at intermediate concentrations. At concentrations below 10μ M metabolic pathways other than a-hydroxylation seem to be of greater importance. Hie toxicologkal evaluation of the high intestinal first-pass metabolism of NDPA, NDBA and NDAA must await the identification and quantitation of the metabolites formed.