Richter E, Richter-Cooberg U, Feng X, Schulze J, Wiessler M
Carcinogenesis. 1986 Jul;7(7):1207-13. doi: 10.1093/carcin/7.7.1207.
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.
已在大鼠小肠中研究了亚硝胺结构与代谢之间的可能关系。用含有四种对称二烷基亚硝胺（每个侧链含2 - 5个碳原子，所有α位均用14C标记）之一或两种不对称亚硝胺（N-亚硝基叔丁基甲胺和N-亚硝基甲基苄胺，甲基用14C标记）的台氏液从肠腔侧对空肠和回肠的分离段进行2小时灌注。除了测量14CO2的产生以及14C与肠组织的共价结合外，还通过高效液相色谱法分析吸收液（吸收物）以及灌注介质和组织匀浆中极性代谢物的存在，以评估亚硝胺的肠道代谢。N-亚硝基二乙胺和两种不对称亚硝胺均未发生显著代谢。随着对称二烷基亚硝胺链长的增加，小肠代谢显著增加。在1微摩尔浓度下，空肠段和回肠段中分别有高达60%和30%的N-亚硝基二丙胺（NDPA）以及两个肠段中超过90%的N-亚硝基二丁胺（NDBA）和N-亚硝基二戊胺（NDAA）在吸收过程中被代谢。在灌注液和组织匀浆中也发现了代谢物，但与吸收物相比，其比例通常较低。随着浓度的增加，代谢物的比例下降，回肠段的下降比空肠段更明显。在回肠段，CO2的产生和共价结合可忽略不计，但在用NDPA、NDBA或NDAA灌注的空肠段中，其含量分别高达剂量的5 - 8%和0.1 - 0.4%。对于NDBA和NDAA，未观察到浓度依赖性下降，在中间浓度下发现14CO2和结合14C的量最高。在浓度低于10微摩尔时，除α-羟基化以外的代谢途径似乎更为重要。对NDPA、NDBA和NDAA肠道首过代谢率高的毒理学评估必须等待对所形成代谢物的鉴定和定量。
