Inhibitory effects of idoxifene on hepatic fibrosis in rats.
OBJECTIVE
To investigate the effects of a tissue-specific selective estrogen receptor modulator, idoxifene, on hepatic fibrosis in rats.


METHODS
Hepatic fibrosis was induced by dimethylnitrosamine (DMN) in male rats. The DMN model of hepatic fibrosis and the hepatocytes undergoing oxidative stress were treated with idoxifene respectively. The effect of idoxifene on hepatic fibrosis in the DMN model was examined by immunohistochemistry. Effects of idoxifene on antioxidant enzyme levels of copper, zinc-dependent superoxide dismutase (CuZn-SOD), and cellular glutathione peroxidase (GSHPx) were measured by ELISA. Effects of idoxifene on activation, proliferation, and apoptosis of culture-activated hepatic stellate cells (HSC) were analysed by immunohistochemistry, bromodeoxyuridine (BrdU) uptake, and flow cytometry, respectively.


RESULTS
Idoxifene could markedly suppress DMN-induced hepatic fibrosis in male rats. A treatment of 0.4 mg x kg(-1) x d(-1) of idoxifene reduced the protein levels of collagen in the DMN model by 41.19% (P<0.05). Protein level of CuZn-SOD and activitiy of GSHPx in liver treated with DMN plus 0.4 mg/kg/d of idoxifene were 2.65 times (P<0.05) and 2.08 times greater (P<0.05) than that of liver treated with DMN alone respectively. The protein level of CuZn-SOD and activity of GSHPx in cultured rat hepatocytes treated with ferric nitrilotriacetate (FeNTA) plus 1 multiply 10(-7) mol/L of idoxifene were 3.43 times (P<0.05) and 2.52 times (P<0.05) greater than that treated with FeNTA alone. Idoxifene could inhibit HSC activation. Compared with the control, the uptake of BrdU in HSC cultured with 1 multiply 10(-7) mol/L of idoxifene was reduced by 51.87 % (P<0.05), and the number of apoptotic HSCs cultured with 1 multiply 10(-7) mol/L of idoxifene increased by 94.52% (P<0.05).


CONCLUSIONS
Idoxifene showed inhibitory action on hepatic fibrosis in male rats.
Zhou
Ya-jun
YJ
Department of Biochemistry and Molecular Biology, Medical College, Nan Tong University, Nantong 226001, China. zhouyajun64@hotmail.com
Yin
Dong-mei
DM
Chen
Hong-shan
HS
Shi
Jian-hua
JH
Sha
Bao-xi
BX
Wang
Xing
X
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004128:Dimethylnitrosamine; D005979:Glutathione Peroxidase / Q000378:metabolism; D022781:Hepatocytes; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D024042:Collagen Type I; D013629:Tamoxifen; C071362:idoxifene; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D004128:Dimethylnitrosamine