Carcinogenesis 1986-07-01

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

E Richter, U Richter-Cooberg, X Feng, J Schulze, M Wiessler

文献索引：Carcinogenesis 7(7) , 1207-13, (1986)

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摘要

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 14C-labeled at the alpha position, or one of two unsymmetrical nitrosamines, N-nitroso-tert-butylmethylamine and N-nitrosomethylbenzylamine, 14C-labeled in the methyl group. Besides measurement of 14CO2 production and covalent binding of 14C to intestinal tissue, the absorbed fluid (absorbate) as well as the perfusion medium and tissue homogenates 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 microM up to 60% and 30% of N-nitrosodipropylamine (NDPA) in jejunal and ileal segments, respectively, and greater than 90% of N-nitrosodibutylamine (NDBA) and N-nitrosodipentylamine (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. CO2 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 14CO2 and bound 14C being found at intermediate concentrations. At concentrations below 10 microM metabolic pathways other than alpha-hydroxylation seem to be of greater importance. The toxicological evaluation of the high intestinal first-pass metabolism of NDPA, NDBA and NDAA must await the identification and quantitation of the metabolites formed.