Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: Implications for estrogen-induced initiation of renal tumors
Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: Implications for estrogen-induced initiation of renal tumors
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DOI：
10.1021/tx010042g
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发表时间：
2001-08-01
影响因子：
4.1
通讯作者：
Rogan, EG
中科院分区：
文献类型：
--
作者：
Cavalieri, EL;Kumar, S;Rogan, EG
内源性儿茶酚雌激素醌（CE-Q）与DNA的反应可能通过产生致癌突变而引发癌症。用雌激素或4-儿茶酚雌激素（4-CE）（而不是2-CE）治疗雄性叙利亚金仓鼠，诱导肾脏肿瘤，而不是肝脏肿瘤。仓鼠为研究雌激素代谢物的激活和失活（保护）与CE-Q形成的关系提供了一个极好的模型。有几个因素可以使雌激素稳态失衡，从而增加导致致癌CE-3，4-Q的氧化途径。仓鼠注射8 μ mol的雌二醇（E-2）和肝脏和肾脏提取物进行了分析31雌激素代谢产物，共轭物，和脱嘌呤DNA加合物的HPLC电化学检测。肝脏和肾脏均不含4-甲氧基CE，推测是由于2-CE对儿茶酚-O-甲基转移酶的已知抑制作用。在肝脏中观察到更多的2-CE O-甲基化，在肾脏中观察到更多的CE-Q形成。这些结果表明，在肾脏中，2-CE的保护性甲基化程度较低，CE氧化为CE-Q的程度更明显。为了进一步研究这一点，用L-丁硫氨酸（SR）-亚砜亚胺预处理仓鼠，以消耗谷胱甘肽水平，然后用E2处理。与肝脏相比，在肾脏中观察到非常低水平的CE和甲氧基CE，表明几乎没有保护性还原酶活性。最重要的是，在肾脏中检测到CE-3，4-Q与DNA反应形成脱嘌呤的4-羟基E（2）（E-1）1-N7 Gua加合物，但在肝脏中未检测到。因此，肾脏中肿瘤的发生似乎是由于肾脏中2-CE的甲基化相对较差和还原酶活性较差引起的，从而导致高水平的CE-Q。因此，由CE-3，4-Q形成脱嘌呤DNA加合物可能是雌激素诱导的肾肿瘤发生的第一个关键事件。
Reaction of endogenous catechol estrogen quinones (CE-Q) with DNA may initiate cancer by generation of oncogenic mutations. Treatment of male Syrian golden hamsters with estrogens or 4-catechol estrogens (4-CE), but not 2-CE, induces kidney, but not liver, tumors. The hamster provides an excellent model for studying activation and deactivation (protection) of estrogen metabolites in relation to formation of CE-Q. Several factors can unbalance estrogen homeostasis, thereby increasing the oxidative pathway leading to the carcinogenic CE-3,4-Q. Hamsters were injected with 8 mu mol of estradiol (E-2) and liver and kidney extracts were analyzed for 31 estrogen metabolites, conjugates, and depurinating DNA adducts by HPLC with electrochemical detection. Neither liver nor kidney contained 4-methoxyCE, presumably due to the known inhibition of catechol-O-methyltransferase by 2-CE. More O-methylation of 2-CE was observed in the liver and more formation of CE-Q in the kidney. These results suggest less protective methylation of 2-CE and more pronounced oxidation of CE to CE-Q in the kidney. To investigate this further, hamsters were pretreated with L-buthionine(SR)-sulfoximine to deplete glutathione levels and then treated with E2. Compared to the liver, a very low level of CE and methoxyCE was observed in the kidney, suggesting little protective reductase activity. Most importantly, reaction of CE-3,4-Q with DNA to form the depurinating 4-hydroxyE(2)(E-1)1-N7Gua adducts was detected in the kidney, but not in the liver. Therefore, tumor initiation in the kidney appears to arise from relatively poor methylation of 2-CE and poor reductase activity in the kidney, resulting in high levels of CE-Q. Thus, formation of depurinating DNA adducts by CE-3,4-Q may be the first critical event in the initiation of estrogen-induced kidney tumors.