Journal Article

Inhibition of TGF-β-induced apoptosis by ethinyl estradiol in cultured, precision cut rat liver slices and hepatocytes

Jinqiang Chen, Mamata Gokhale, Brian Schofield, Shelly Odwin and James D. Yager

in Carcinogenesis

Volume 21, issue 6, pages 1205-1211
Published in print June 2000 | ISSN: 0143-3334
Published online June 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.6.1205
Inhibition of TGF-β-induced apoptosis by ethinyl estradiol in cultured, precision cut rat liver slices and hepatocytes

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Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis in the rat. Treatment with EE and other hepatic promoters induces transient growth stimulation followed by growth inhibition (mitosuppression) in hepatocytes. Previously, we identified several genes whose transcript levels were increased during EE-induced mitosuppression, including transforming growth factor β (TGF-β), which inhibits growth and induces apoptosis in hepatocytes. Various hepatic promoters, including phenobarbital and several peroxisomal proliferators, have been shown to inhibit TGF-β-induced apoptosis in rat hepatocytes. The goal of this study was to investigate whether EE is also an inhibitor of TGF-β-induced apoptosis in rat hepatocytes. Several approaches to detect apoptosis were used, including the TUNEL assay, detection of high molecular weight DNA fragmentation by field inversion gel electrophoresis and determination of cytosolic cytochrome c levels by western analysis. TGF-β-induced apoptosis in cultured, precision cut liver slices and hepatocytes of female rats. EE (≤3 μM) completely inhibited TGF-β-induced apoptosis in these systems in the absence of cytotoxicity. These findings add EE to the list of several hepatic promoters that both induce TGF-β while simultaneously inhibiting its ability to cause apoptosis.

Keywords: EE, ethinyl estradiol; E2, estradiol; HMW, high molecular weight; ITS, 5 μg/ml insulin and transferrin and 5 ng/ml selenous acid; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt; PB, phenobarbital; PBS, phosphate-buffered saline; PI, propidium iodide.

Journal Article.  6370 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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