Taurog A, Dorris M L
Department of Pharmacology, University of Texas Health Science Center, Dallas 75235.
Endocrinology. 1988 Feb;122(2):592-601. doi: 10.1210/endo-122-2-592.
We have developed HPLC procedures for analyzing the metabolites of [35S]methylmercaptoimidazole [( 35S] MMI) and [35S]propylthiouracil [( 35S]PTU) in bile, urine, serum, and liver of rats. We also studied urinary metabolites of [35S] MMI and [35S]PTU in one human subject. In bile collected from [35S]MMI-injected rats, two major metabolites accounted for 80-90% of the total 35S. Incubation of these metabolites either with or without beta-glucuronidase led to the appearance of a 35S-labeled compound less polar than MMI. In contrast, the major [35S]PTU metabolite in bile (greater than 50% of total 35S) was completely converted to [35S]PTU on incubation with beta-glucuronidase and showed no conversion in a control incubation. From these results we conclude that the major biliary metabolites of MMI in rats are not glucuronides. They appear to be labile conjugates of a metabolite of MMI. After [35S]MMI injection into rats, two major and at least four minor metabolites were observed in urine. In one human who received [35S]MMI orally, the HPLC profile of 35S in urine was similar to that of the rat. Incubation of human urine or of its isolated major component with beta-glucuronidase had no significant effect on the HPLC profile. On the other hand, the major urinary metabolite of [35S]PTU in human and rat urine was completely converted to [35S]PTU on incubation of whole urine with beta-glucuronidase. These results indicate that glucuronides comprise at most only a minor fraction of MMI metabolites in urine of rats or humans. Based on similarities in elution time, the metabolites of [35S]PTU in urine closely resembled those in bile of rats. In contrast, the metabolites of [35S]MMI in urine were strikingly different from those in bile. PTU displays noncovalent binding to serum protein to a much greater extent than does MMI. However, after injection of [35S]MMI into rats, a significant fraction of the 35S was firmly bound to protein in both serum and liver. This binding appeared to be covalent and involved metabolism of [35S]MMI. This type of binding was much less detectable after the injection of [35S]PTU into rats.
我们已开发出高效液相色谱法（HPLC）程序，用于分析大鼠胆汁、尿液、血清和肝脏中[35S]甲基巯基咪唑[（35S）MMI]和[35S]丙硫氧嘧啶[（35S）PTU]的代谢产物。我们还研究了一名人类受试者尿液中[35S]MMI和[35S]PTU的代谢产物。在从注射了[35S]MMI的大鼠收集的胆汁中，两种主要代谢产物占总35S的80 - 90%。这些代谢产物与或不与β - 葡萄糖醛酸酶一起孵育，都会产生一种极性比MMI小的35S标记化合物。相比之下，胆汁中主要的[35S]PTU代谢产物（占总35S的50%以上）在与β - 葡萄糖醛酸酶孵育时完全转化为[35S]PTU，而在对照孵育中未显示转化。根据这些结果，我们得出结论，大鼠中MMI的主要胆汁代谢产物不是葡萄糖醛酸苷。它们似乎是MMI一种代谢产物的不稳定共轭物。给大鼠注射[35S]MMI后，在尿液中观察到两种主要代谢产物和至少四种次要代谢产物。在一名口服[35S]MMI的人类受试者中，尿液中35S的HPLC图谱与大鼠的相似。人尿或其分离出的主要成分与β - 葡萄糖醛酸酶一起孵育，对HPLC图谱没有显著影响。另一方面，人尿和大鼠尿中[35S]PTU的主要尿液代谢产物在全尿与β - 葡萄糖醛酸酶孵育时完全转化为[35S]PTU。这些结果表明，葡萄糖醛酸苷在大鼠或人类尿液中MMI代谢产物中最多只占一小部分。根据洗脱时间的相似性，尿液中[35S]PTU的代谢产物与大鼠胆汁中的代谢产物非常相似。相比之下，尿液中[35S]MMI的代谢产物与胆汁中的代谢产物明显不同。PTU与血清蛋白的非共价结合程度比MMI大得多。然而，给大鼠注射[35S]MMI后，相当一部分35S在血清和肝脏中都与蛋白质牢固结合。这种结合似乎是共价的，并且涉及[...完整内容请参考原文，此处省略部分英文原文内容...][35S]MMI的代谢。给大鼠注射[35S]PTU后，这种结合类型较难检测到。
