Basic Research
Copyright ©The Author(s) 2004. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 1, 2004; 10(9): 1315-1320
Published online May 1, 2004. doi: 10.3748/wjg.v10.i9.1315
Suppressive effects of 17β-estradiol on hepatic fibrosis in CCl4-induced rat model
Qing-Hua Liu, Ding-Guo Li, Xin Huang, Chun-Hua Zong, Qin-Fang Xu, Han-Ming Lu
Qing-Hua Liu, Ding-Guo Li, Xin Huang, Chun-Hua Zong, Qin-Fang Xu, Han-Ming Lu, Department of Gastroenterology, Xinhua Hospital of Shanghai Secondary Medical University, Shanghai 200092, China
Author contributions: All authors contributed equally to the work.
Supported by National Natural Science Foundation of China, No. 30170411
Correspondence to: Dr. Ding-Guo Li, Department of Gastroenterology, Xinhua Hospital of Shanghai Secondary Medical University, Shanghai 200092, China. dingguo_li@yahoo.com.cn
Telephone: +86-21-65790000-5316 Fax: +86-21-55055127
Received: August 11, 2003
Revised: September 20, 2003
Accepted: October 12, 2003
Published online: May 1, 2004
Abstract

AIM: To investigate the pathway via which 17β-estradiol (β-Est) exerts suppressive effects on rat hepatic fibrosis.

METHODS: In vivo study was done in CCl4-induced female hepatofibrotic rats. Fibrosis-suppressive effect of β-Est (20 μg/kg·d) was evaluated in intact and ovariectomized rat models. Six weeks after the treatment, all the rats were sacrificed and specimens of serum or liver tissue were collected for the studies. Serum liver enzymes, fibrosis markers and estradiol levels were determined by standard enzymatic methods, ELISA and RIA, respectively. Degrees of fibrosis and areas of hepatic stellate cells (HSCs) positive for alpha-smooth muscle actin (α-SMA) in the liver were determined by van Gieson (VG) stain and immunohistochemistry. In vitro studies, HSCs were isolated by a combination of pronase-collagenase perfusion and density gradient centrifugation. First-passage HSCs were randomly divided into 10 groups, and different concentrations of β-Est, 2-hydroxyestradiol (2OHE) or 2-methoxyestradiol (2MeOE) were separately added to the cell groups. After incubation for 72 h, the degree of cell proliferation, collagen production, α-SMA or estrogen receptor (ER) expression was determined by MTT assay, ELISA and immunohistochemistry, respectively.

RESULTS: β-Est treatment reduced aspartate aminotransfer-ase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA) and type IV collagen (C IV) in sera, suppressed hepatic collagen content, decreased the areas of HSCs positive for α-SMA significantly in both intact and ovariectomized female hepatofibrotic rats. There was a negative correlation between the percentage of fibrotic area of liver tissue and the serum estradiol level; the calculated correlation coefficient was -0.57 (P < 0.01). β-Est and its metabolites concentration-dependently (10-9 mol/L-10- 7 mol/L) inhibited HSC proliferation and collagen synthesis. At the concentration of 10-7 mol/L, they could inhibit α-SMA expression. The order of potency was 2MeOE > 2OHE > β-Est.

CONCLUSION: β-Est may suppress hepatic fibrosis probably via its biologically active metabolites.

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