Godeneche D, Madelmont J C, Moreau M F, Duprat J, Plagne R, Meyniel G
Drug Metab Dispos. 1986 Jan-Feb;14(1):112-7.
Previously we have shown that a new nitrosourea, 2-chloroethyl nitrosocarbamoylcystamine (CNCC), undergoes an extensive metabolism in the rat. Two pairs of plasma metabolites have been identified. This suggested our hypothesis that the metabolic pathway involves the reduction of the disulfur bridge followed by the methylation and the oxidation of the thiol groups. The two first intermediates, i.e. the unoxidized metabolites, could not be detected in vivo. Hence, to better understand and to confirm the proposed mechanism of biotransformation of CNCC, its in vitro metabolism has been studied. Incubation of CNCC with a rat liver homogenate or a 10,000g supernatant fraction leads to the formation of four pairs of metabolites. Among them we have identified the two first intermediates not found in vivo and the oxidized metabolites. These findings, together with the kinetics data, suggest that reduction, methylation, and oxidation are very rapid enzymatic reactions. We also show that, for completion of the reaction, the incubation mixture had to contain a cytosolic thioreductase, a microsomal and cytosolic S-methyltransferase, a microsomal oxidase, and an NADPH generating system. The sum of the amounts of metabolites found in the organic extratable material is less than the amount of CNCC metabolized. We conclude that the biotransformation of CNCC proceeds from two fast competitive mechanisms operative on both the disulfur and the nitroso groups.
此前我们已经表明，一种新的亚硝基脲，即2-氯乙基亚硝基氨基甲酰胱胺（CNCC），在大鼠体内会经历广泛的代谢。已经鉴定出两对血浆代谢物。这提示了我们的假设，即代谢途径涉及二硫键的还原，随后是硫醇基团的甲基化和氧化。两种最初的中间体，即未氧化的代谢物，在体内无法检测到。因此，为了更好地理解和确认所提出的CNCC生物转化机制，我们研究了其体外代谢。将CNCC与大鼠肝脏匀浆或10,000g上清液部分一起孵育会导致形成四对代谢物。其中我们鉴定出了在体内未发现的两种最初中间体以及氧化代谢物。这些发现，连同动力学数据，表明还原、甲基化和氧化是非常快速的酶促反应。我们还表明，为了使反应完成，孵育混合物必须含有一种胞质硫氧还蛋白还原酶、一种微粒体和胞质S-甲基转移酶、一种微粒体氧化酶以及一个NADPH生成系统。在有机可萃取物中发现的代谢物总量少于代谢的CNCC量。我们得出结论，CNCC的生物转化是由作用于二硫键和亚硝基的两种快速竞争机制进行的。
