Keefer L K, Anjo T, Heur Y H, Yang C S, Mico B A
Chemistry Section, National Cancer Institute, Frederick Cancer Research Facility, MD 21701.
IARC Sci Publ. 1987(84):113-6.
Enzymatic cleavage of N-nitrosodimethylamine (NDMA) to nitrite (normally representing about 10% of the total metabolism in vitro) also produces methylamine in yields roughly equimolar to those of nitrite, suggesting that the 'denitrosation' pathway may be responsible for the previously unexplained detection of methylamine as a urinary metabolite of NDMA and, at least in part, for the recovery of less than stoichiometric amounts of dinitrogen in 15N-labelling experiments. We have now followed excretion of labelled methylamine by rats receiving 14C-NDMA as a possible index of the extent of in-vivo denitrosation. Correcting for the proportion of labelled methylamine recovered in the urine following its administration under the conditions used for NDMA, 2.5-10% of the NDMA metabolism in Fischer rats appeared to proceed by a methylamine-forming route. The results are consistent with the conclusion that the metabolism of NDMA is best viewed as a competition between two pathways, with denitrosation diverting a significant proportion of the clearance to a presumably deactivating metabolic route at the expense of the activating alkylation pathway responsible for carcinogenesis.
N-亚硝基二甲胺（NDMA）酶解生成亚硝酸盐（在体外通常约占总代谢量的10%）时，还会生成与亚硝酸盐产量大致等摩尔的甲胺，这表明“脱亚硝化”途径可能是之前无法解释的将甲胺作为NDMA尿液代谢物检测到的原因，并且至少部分地解释了在15N标记实验中回收的二氮量少于化学计量的情况。我们现在追踪了接受14C-NDMA的大鼠体内标记甲胺的排泄情况，以此作为体内脱亚硝化程度的一个可能指标。根据在NDMA使用条件下给药后尿液中回收的标记甲胺比例进行校正后，在Fischer大鼠中，2.5 - 10%的NDMA代谢似乎是通过生成甲胺的途径进行的。这些结果与以下结论一致，即NDMA的代谢最好被视为两条途径之间的竞争，脱亚硝化将相当一部分清除过程转移到可能是失活的代谢途径，而牺牲了负责致癌作用的活化烷基化途径。
