Chander Surinder K, Purohit Atul, Woo L W Lawrence, Potter Barry V L, Reed Michael J
Endocrinology and Metabolic Medicine and Sterix Ltd, Faculty of Medicine, Imperial College, St. Mary's Hospital, London W2 1NY, UK.
Biochem Biophys Res Commun. 2004 Sep 10;322(1):217-22. doi: 10.1016/j.bbrc.2004.07.108.
Oestrogen sulphamates have increased systemic, but reduced hepatic oestrogenicity which results from their sequestration and transport through the liver by red blood cells. Oestrogen sulphamates act as prodrugs for the release of natural oestrogens but, as yet, there is little information as to how the sulphamoyl moiety is cleaved from the steroid nucleus. In the present investigation we have used the potent steroid sulphatase (STS) inhibitor, 667 COUMATE, to explore the possibility that STS might be responsible for the hydrolysis of oestrogen sulphamates. Administration of oestrone sulphamate (10 microg/day, s.c., for 5 days) to ovariectomised rats resulted in a 3.5-fold increase in the uterine weights of treated animals. Co-administration of oestrone sulphamate and 667 COUMATE (2 mg/kg) completely blocked STS activity in treated animals and completely abrogated the ability of oestrone sulphamate to stimulate uterine growth. In vitro studies, using [(3)H]oestrone sulphamate or [(3)H]oestrone, revealed that the uptake of the sulphamate derivative (95.9+/-2.4%) by red blood cells was considerably higher than that for the non-sulphamoylated oestrogen (25.1+/-1.9%). Results from these studies demonstrate convincingly that STS is the enzyme responsible for the removal of the sulphamoyl group from oestrogen sulphamates. This enzyme therefore has a crucial role in regulating the oestrogenicity associated with this class of drug.
硫酸化雌激素增加了全身的雌激素活性，但降低了肝脏的雌激素活性，这是由于它们被红细胞隔离并通过肝脏运输所致。硫酸化雌激素作为天然雌激素释放的前体药物，但目前关于硫酸酰基部分如何从甾体核上裂解下来的信息很少。在本研究中，我们使用了强效的甾体硫酸酯酶（STS）抑制剂667香豆酸，来探讨STS是否可能负责硫酸化雌激素的水解。给去卵巢大鼠皮下注射硫酸雌酮（10微克/天，共5天），导致处理组动物子宫重量增加了3.5倍。同时给予硫酸雌酮和667香豆酸（2毫克/千克）完全阻断了处理组动物的STS活性，并完全消除了硫酸雌酮刺激子宫生长的能力。使用[³H]硫酸雌酮或[³H]雌酮进行的体外研究表明，红细胞对硫酸酯衍生物的摄取（95.9±2.4%）明显高于非硫酸化雌激素（25.1±1.9%）。这些研究结果令人信服地证明，STS是负责从硫酸化雌激素中去除硫酸酰基的酶。因此，这种酶在调节与这类药物相关的雌激素活性方面起着关键作用。
