Zhu B T, Liehr J G
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Toxicol Appl Pharmacol. 1994 Mar;125(1):149-58. doi: 10.1006/taap.1994.1059.
Catechol estrogens have been postulated to mediate estradiol-induced kidney tumorigenesis in Syrian hamsters. As part of an examination of this postulate, we studied the influence of quercetin, a polyphenolic flavonoid, on the incidence and severity of estrogen-induced kidney tumors, on the metabolic activation of estradiol to catechol estrogens, and on the inactivation of catechol estrogens by catechol-O-methyltransferase-mediated O-methylation. None of the hamsters treated with 0.3 or 3% quercetin in the diet for 5.7 or 6.5 months, respectively, developed tumors, whereas all animals treated with estradiol developed kidney tumors. The coadministration of estradiol plus 3% quercetin significantly (p < 0.05) increased the mean number of large tumor nodules and the incidence of abdominal metastases over values obtained with hormone treatment alone. The coadministration of estradiol plus 0.3 or 3% quercetin for 16 days increased renal NADPH-dependent estradiol-4- but not estradiol-2-hydroxylase activities by 91 or 73%, respectively, over values obtained with hormone treatment alone. In vitro, quercetin and its structural analog, fisetin, strongly inhibited the catechol-O-methyltransferase-catalyzed O-methylation of 60 microM 4-hydroxyestradiol, with IC50 values of approximately 2-4 microM. Kinetic analyses of the enzyme inhibition by quercetin and fisetin revealed a mixed-type of inhibition (competitive plus non-competitive). Combined treatment of estradiol plus 3% quercetin decreased the rates of kidney catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by 34 and 22%, respectively, from values obtained with hormone treatment alone. Rates of hamster liver and kidney microsome-mediated estrogen quinone formation and quinone reduction (redox cycling) in estradiol plus 3% quercetin-treated hamsters were not markedly altered compared to values obtained in estradiol-treated animals. It is concluded that increased rates of formation of 4-hydroxyestradiol combined with an inhibition of the inactivation of this catechol estrogen by catechol-O-methyltransferase may result in elevated levels of this estrogen metabolite, specifically in the hamster kidney, where it may undergo metabolic redox cycling and generate potentially mutagenic free radicals. Thus, the potentiation by quercetin of estradiol-induced tumorigenesis in hamster kidney supports a role of 4-hydroxyestradiol in estrogen-induced carcinogenesis in this species.
儿茶酚雌激素被认为在叙利亚仓鼠中介导雌二醇诱导的肾肿瘤发生。作为对这一假设研究的一部分，我们研究了槲皮素（一种多酚类黄酮）对雌激素诱导的肾肿瘤的发生率和严重程度、雌二醇向儿茶酚雌激素的代谢活化以及儿茶酚-O-甲基转移酶介导的O-甲基化对儿茶酚雌激素失活的影响。分别在饮食中添加0.3%或3%槲皮素处理5.7或6.5个月的仓鼠均未发生肿瘤，而所有接受雌二醇处理的动物都发生了肾肿瘤。雌二醇与3%槲皮素联合给药显著（p<0.05）增加了大肿瘤结节的平均数量以及腹部转移的发生率，高于单独激素治疗的值。雌二醇与0.3%或3%槲皮素联合给药16天，使肾脏中依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的雌二醇-4-羟化酶活性分别比单独激素治疗的值提高了91%或73%，但雌二醇-2-羟化酶活性未提高。在体外，槲皮素及其结构类似物漆黄素强烈抑制儿茶酚-O-甲基转移酶催化的60微摩尔4-羟基雌二醇的O-甲基化，半数抑制浓度（IC50）值约为2 - 4微摩尔。槲皮素和漆黄素对该酶抑制作用的动力学分析显示为混合型抑制（竞争性加非竞争性）。雌二醇与3%槲皮素联合治疗使肾脏中儿茶酚-O-甲基转移酶催化的2-羟基雌二醇和4-羟基雌二醇的O-甲基化速率分别比单独激素治疗的值降低了34%和22%。与接受雌二醇治疗的动物相比，接受雌二醇加3%槲皮素治疗的仓鼠肝脏和肾脏微粒体介导的雌激素醌形成和醌还原（氧化还原循环）速率没有明显改变。结论是，4-羟基雌二醇形成速率的增加，再加上儿茶酚-O-甲基转移酶对这种儿茶酚雌激素失活的抑制作用，可能导致这种雌激素代谢物水平升高，特别是在仓鼠肾脏中，在那里它可能经历代谢氧化还原循环并产生潜在的致突变自由基。因此，槲皮素增强雌二醇诱导的仓鼠肾肿瘤发生支持了4-羟基雌二醇在该物种雌激素诱导的致癌作用中的作用。
