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Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Antioxidant and anti-apoptotic activities of estradiol in rat fibrotic liver and in cultured rat hepatocytes

I Shimizu MD 1, T Omoya MD 1, Y Zhou PhD 1, M Itonaga BS 1, Y Okamura BS 2, M Shono PhD 2, M Nakazono MD 1, H Honda MD 1, M Nomura MD 1, S Ito MD 1

1 Second Dept Internal Medicine,, 2 General Laboratory for Medical Research, Tokushima University School of Medicine, Tokushima, Japan, shimizui@clin.med.tokushima-u.ac.jp

AIMS: Oxidative stress has a causative role in the development of hepatic fibrosis and apoptosis, and NF-kappaB is a key transcription factor that induces multiple genes in response to inflammation or oxidative stress. We previously reported that estradiol inhibited activation of rat hepatic stellate cells in vivo and in vitro. It should be noted that estradiol is a potent endogenous antioxidant. The aim of this study was to obtain information on the beneficial role of estradiol in the liver. METHODS: The inhibitory effects of estradiol on NF-kappaB activation, apoptosis, and oxidative stress were explored using experimental rat fibrotic livers and cultured rat hepatocytes undergoing oxidative stress. RESULTS: Hepatic levels of collagen and malondialdehyde were decreased and hepatic levels of superoxide dismutase and glutathione peroxidase were increased by the presence of estradiol in the experimental fibrosis model. The antioxidant enzyme response of cultured hepatocytes to oxidative stress was significantly improved by estradiol in a dose-dependent manner. Estradiol was also observed to induce Bcl-2 expression in the injured livers and cultured hepatocytes, to have no adverse effects, and to act as an inhibitor early in the apoptotic pathway. In addition, treatment with estradiol inhibited the IkB-alpha degradation and NF-kappaB activation with attenuation of hepatocyte oxidative bursts. The hepatoprotective effect of estradiol was greater than that observed for the same dose of tamoxifen. CONCLUSIONS: These findings suggest that estradiol may enhance biological defense activities against oxidative stress and protect hepatocytes from inflammatory cell injury and early apoptosis.

KEY WORDS: lipid peroxidation, cytoprotection, estradiol, apoptosis, liver fibrosis.

For more information, contact shimizui@clin.med.tokushima-u.ac.jp

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on synergistic therapies.

http://www.cancerprev.org/Journal/Issues/24/101/410/3380