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National Institute of Environmental Health Sciences

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Publication Detail

Title: Increased mitochondrial superoxide production in rat liver mitochondria, rat hepatocytes, and HepG2 cells following ethinyl estradiol treatment.

Authors: Chen, J; Li, Y; Lavigne, J A; Trush, M A; Yager, J D

Published In Toxicol Sci, (1999 Oct)

Abstract: 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 microM levels) and time-dependent response. Inhibition of P450-mediated estrogen metabolism inhibited, while direct exposure to E2 catechol metabolites enhanced LDCL. Co-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.

PubMed ID: 10543024 Exiting the NIEHS site

MeSH Terms: Animals; Carcinoma, Hepatocellular/metabolism; Catechol O-Methyltransferase Inhibitors; Catechol O-Methyltransferase/metabolism; Cells, Cultured; Estradiol Congeners/toxicity*; Estradiol/analogs & derivatives; Estradiol/pharmacology; Estrogen Receptor Modulators/pharmacology; Ethinyl Estradiol/toxicity*; Fulvestrant; Glutathione/deficiency; Glutathione/metabolism; Liver Neoplasms/enzymology; Liver Neoplasms/metabolism; Liver/cytology; Liver/drug effects*; Liver/enzymology; Liver/metabolism*; Male; Mitochondria, Liver/drug effects*; Mitochondria, Liver/metabolism*; Rats; Rats, Inbred F344; Superoxides/metabolism*; Tumor Cells, Cultured

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