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ToxSci Advance Access published online on July 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg183
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 11, 2003; accepted June 23, 2003
© 2003 Society of Toxicology

Carcinogenicity

Enhanced Mitochondrial Gene Transcript, ATP, Bcl-2 Protein Levels, and Altered Glutathione Distribution in Ethinyl Estradiol-Treated Cultured Female Rat Hepatocytes

Jinqiang Chen 1, Michael Delannoy 2, Shelly Odwin 1, Ping He 3, Michael A. Trush 1, and James D. Yager 1*

1 Department of Environmental Health Sciences, Division of Toxicological Sciences, The Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD, 21205-2179, U.S.A.
2 Electron and Confocal Microscopy Laboratory, Department of Physiology, The Johns Hopkins School of Medicine, 625 North Wolfe Street, Baltimore, MD, 21205
3 Department of Environmental Health Sciences, Division of Toxicological Sciences, The Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD, 21205-2179, U.S.A.

* To whom correspondence should be addressed. E-mail: jyager{at}jhsph.edu.


  Abstract

Ethinyl estradiol (EE) is a strong promoter and weak hepatocarcinogen in rats. Previously, we demonstrated that EE enhanced the transcript levels of nuclear genome and mitochondrial genome encoded genes and respiratory chain activity in female rat liver and also inhibited TGF-{beta}-induced apoptosis in cultured liver slices and hepatocytes from female rats. In this study, using cultured female rat hepatocytes, we observed that EE, within 24 h, increased the transcript levels of mitochondrial genome-encoded genes cytochrome oxidase subunits I, II, and III. This effect was accompanied by increased mitochondrial respiratory chain activity, as reflected by increased mitochondrial superoxide generation, detected by lucigenin-derived chemiluminescence, and cellular ATP levels. EE also enhanced the levels of Bcl-2 protein. Biochemical analyses indicated that EE significantly increased both the levels of glutathione (reduced [GSH] and oxidized [GSSG] forms) per mg protein in mitochondria and nuclei while the % of total glutathione in the oxidized form was not affected. This finding was supported by confocal microscopy. These effects caused by EE may contribute, at least in part, to the EE-mediated inhibition of hepatic apoptosis.


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