Ebner T, Remmel R P, Burchell B
Department of Biochemical Medicine, Ninewells Medical School, University of Dundee, Scotland, UK.
Mol Pharmacol. 1993 Apr;43(4):649-54.
The synthetic estrogen ethinylestradiol is extensively eliminated as glucuronide metabolites in humans, but the UDP-glucuronosyltransferases (UGTs) catalyzing this reaction have not been identified. Therefore, ethinylestradiol was tested as a substrate for cloned human UGTs stably expressed in V79 cell lines. Two cloned expressed human enzymes, a bilirubin UGT and a phenol UGT, were observed to catalyze the glucuronidation of ethinylestradiol. High performance liquid chromatographic analysis of the products formed revealed that the expressed bilirubin UGT specifically produced ethinylestradiol-3-glucuronide. In human liver microsomes the ratio of 3-glucuronide/17-glucuronide was 97:3. Subsequent study of the cloned expressed enzymes and human liver microsomes from Crigler-Najjar patients by kinetic analysis and by substrate inhibition strongly indicated that a human liver bilirubin UGT was largely responsible for glucuronidation of ethinylestradiol. These results may provide an explanation for jaundice caused by ethinylestradiol in certain susceptible individuals.
合成雌激素炔雌醇在人体内主要以葡萄糖醛酸代谢物的形式被广泛清除，但催化该反应的尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）尚未被鉴定出来。因此，将炔雌醇作为在V79细胞系中稳定表达的克隆人UGTs的底物进行了测试。观察到两种克隆表达的人酶，一种胆红素UGT和一种酚类UGT，可催化炔雌醇的葡萄糖醛酸化反应。对所形成产物的高效液相色谱分析表明，表达的胆红素UGT特异性地产生炔雌醇-3-葡萄糖醛酸苷。在人肝微粒体中，3-葡萄糖醛酸苷/17-葡萄糖醛酸苷的比例为97:3。随后通过动力学分析和底物抑制对克隆表达的酶以及来自克里格勒-纳贾尔综合征患者的人肝微粒体进行研究，结果强烈表明人肝胆红素UGT在很大程度上负责炔雌醇的葡萄糖醛酸化。这些结果可能为某些易感个体中炔雌醇引起的黄疸提供一种解释。
