Increased mitochondrial superoxide production in rat liver mitochondria, rat hepatocytes, and HepG2 cells following ethinyl estradiol treatment
Increased mitochondrial superoxide production in rat liver mitochondria, rat hepatocytes, and HepG2 cells following ethinyl estradiol treatment
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DOI：
10.1093/toxsci/51.2.224
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发表时间：
1999-10-01
影响因子：
3.8
通讯作者：
Yager, JD
中科院分区：
文献类型：
--
作者：
Chen, JQ;Li, YB;Yager, JD
炔雌醇（Ethinyl estradiol，EE）是肝癌发生的强促进剂。用EE和其他肝脏促进剂治疗大鼠可诱导一种以肝细胞更新减少和生长反应性降低为特征的有丝分裂抑制状态。先前，我们鉴定了几种核和线粒体基因组编码的线粒体基因，其转录物在大鼠和EE处理的HepG 2细胞中EE诱导的肝有丝分裂抑制期间增加（Chen等人，Carcinogenesis，17，2783-2786，1996和Carcinogenesis，19，101-107，1998）。在培养的大鼠肝细胞和HepG 2细胞中，EE增加了呼吸链活性（反映为线粒体超氧化物产生增加，检测为光泽精衍生的化学发光（LDCL）增加）。在本文中，我们提供了这些影响的额外特征。从EE处理的大鼠中分离的线粒体中检测到LDCL增加，证明这些雌激素对线粒体功能的影响并不局限于培养中的细胞。EE和雌二醇（E2）增加LDCL在培养的大鼠肝细胞和HepG 2细胞中的剂量（从0.25 μ M水平开始）和时间依赖性反应。抑制P450介导的雌激素代谢抑制，而直接暴露于E2儿茶酚代谢产物增强LDCL。GO处理谷胱甘肽酯或与特定的抗雌激素，ICI 182708抑制LDCL，相反，雌激素诱导的LDCL增强谷胱甘肽耗竭，并通过抑制儿茶酚-O-甲基转移酶。这些结果支持了一个工作假设，即在肝细胞中，雌激素治疗诱导的呼吸链活性增加需要代谢为儿茶酚和雌激素受体介导的信号转导途径。
Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis. Treatment of rats with EE and other hepatic promoters induces a mitosuppressed state characterized by decreased hepatocyte turnover and reduced growth responsiveness. Previously, we identified several nuclear and mitochondrial genome-encoded mitochondrial genes whose transcripts were increased during EE-induced hepatic mitosuppression in rats and in EE-treated HepG2 cells (Chen et al. Carcinogenesis, 17, 2783-2786, 1996 and Carcinogenesis, 19, 101-107, 1998). In both cultured rat hepatocytes and HepG2 cells, EE increased respiratory chain activity (reflected by increased mitochondrial superoxide production detected as increased lucigenin-derived chemiluminescence (LDCL). In this paper, we provide additional characterizations of these effects. Increased LDCL was detected in mitochondria isolated from EE-treated rats, documenting that these estrogen effects on mitochondrial function are not confined to cells in culture. EE and estradiol (E2) increased LDCL in cultured rat hepatocytes and HepG2 cells in a dose- (beginning at 0.25 mu M levels) and time-dependent response. Inhibition of P450-mediated estrogen metabolism inhibited, while direct exposure to E2 catechol metabolites enhanced LDCL. Go-treatment with glutathione ester or with the specific antiestrogen, ICI 182708 inhibited LDCL, In contrast, estrogen-induced LDCL was enhanced by glutathione depletion, and by inhibition of catechol-o-methyltransferase. These results support a working hypothesis that in liver cells, increased respiratory chain activity induced by estrogen treatment requires both metabolism to catechols and an estrogen receptor-mediated signal transduction pathway.