Butterworth M, Lau S S, Monks T J
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712, USA.
Carcinogenesis. 1997 Mar;18(3):561-7. doi: 10.1093/carcin/18.3.561.
In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites. Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
在激素介导的致癌作用动物模型中，雄性叙利亚金黄地鼠在长期暴露于17β-雌二醇后会发生肾癌。这种物种和组织特异性的基础尚不清楚。该模型中缺乏关于17β-雌二醇处置的详细信息。由于儿茶酚雌激素与该致癌模型有关，我们研究了17β-雌二醇在叙利亚金黄地鼠体内的代谢和肾毒性，重点是儿茶酚雌激素硫醚的形成。17β-雌二醇（50微摩尔/千克，腹腔注射）是一种轻度肾毒物，可导致γ-谷氨酰转肽酶（γ-GT）、碱性磷酸酶、谷胱甘肽S-转移酶（GST）和葡萄糖的尿排泄显著升高。给予17β-雌二醇（50微摩尔/千克，腹腔注射）后，作为氧化损伤标志物的肾蛋白羰基和脂质氢过氧化物也会增加。用γ-GT抑制剂阿西维辛治疗动物可降低17β-雌二醇介导的肾毒性，这意味着毒性是由需要该酶代谢的代谢产物介导的。给仓鼠注射17β-[14C]雌二醇（100微摩尔/千克）后，5小时后胆汁中回收了9.7%的剂量，大部分（7.9%）为水溶性代谢产物。鉴定出七种儿茶酚雌激素谷胱甘肽缀合物，即2-羟基-1,4-双-（谷胱甘肽-S-基）-17β-雌二醇、2-羟基-4-（谷胱甘肽-S-基）-17β-雌二醇、2-羟基-4-（谷胱甘肽-S-基）-雌酮、4-羟基-1-（谷胱甘肽-S-基）-雌酮、2-羟基-1-（谷胱甘肽-S-基）-雌酮、4-羟基-1-（谷胱甘肽-S-基）-17β-雌二醇和2-羟基-1-（谷胱甘肽-S-基）-17β-雌二醇。在17β-雌二醇剂量为5.4微摩尔/千克时（该剂量反映了仓鼠肾癌模型中的每日暴露水平），5小时内回收了12%的剂量，为2-和4-羟基-17β-雌二醇以及2-和4-羟基雌酮的谷胱甘肽缀合物组合。总之，儿茶酚雌激素在体内发生氧化，随后与谷胱甘肽结合，并且17β-雌二醇以依赖于γ-GT活性的方式成为轻度肾毒物。
