Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats

• Published in: Life sciences (1973) Vol. 74; no. 7; pp. 897 - 907
• Main Authors: Lu, Guangming, Shimizu, Ichiro, Cui, Xuezhi, Itonaga, Mina, Tamaki, Katsuyoshi, Fukuno, Hiroshi, Inoue, Hiroshi, Honda, Hirohito, Ito, Susumu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 02.01.2004
• Subjects: Administration, Oral; Animals; Antioxidants - therapeutic use; Apoptosis; Apoptosis - drug effects; Bcl-2; bcl-Associated Death Protein; bcl-X Protein; Carrier Proteins - metabolism; Dimethylnitrosamine - toxicity; Disease Models, Animal; Drug Therapy, Combination; Estradiol; Estradiol - administration & dosage; Estradiol - therapeutic use; Estrogen Antagonists - therapeutic use; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Glutathione peroxidase; Glutathione Peroxidase - metabolism; Idoxifene; Injections, Intraperitoneal; L-Lactate Dehydrogenase - blood; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - blood; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - pathology; Male; Malondialdehyde - blood; Oxidative stress; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Wistar; Superoxide dismutase; Superoxide Dismutase - metabolism; Tamoxifen - administration & dosage; Tamoxifen - analogs & derivatives; Tamoxifen - therapeutic use; Glutathione peroxidase; Bcl-2; Oxidative stress; Idoxifene; Superoxide dismutase; Estradiol; Apoptosis
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2003.08.004

Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in a rat model of hepatic fibrosis induced with dimethylnitrosamine (DMN), and suppresses activation of the nuclear factor (NF)-κB proinflammatory transcription factor in cultured rat hepatocytes undergoing oxidative stress. This study reports on the antioxidant and antiapoptotic role of idoxifene and E2 in the DMN model of hepatic fibrosis. The DMN model rats were administered with idoxifene or E2, and were examined activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and expression of Bcl-2 family proteins in the liver. During the course of hepatofibrogenesis after DMN treatment, serum levels of lactate dehydrogenase (LDH), a biomarker for necrosis, and hepatic levels of malondialdehyde (MDA), an end product of lipid peroxidation, increased rapidly for 3 days. On day 14, serum LDH levels normalized, and hepatic fibrosis developed with increased levels of MDA and collagen and decreased production of SOD and GPx in the liver. Fibrotic liver also showed downregulation of Bcl-2 and Bcl-X L expression and upregulation of Bad expression. Idoxifene and E2 suppressed DMN-mediated necrosis, lipid peroxidation, the loss of antioxidant enzyme activity, and proapoptotic status in Bcl-2 family protein expression as well as hepatic fibrosis. These findings indicate that, in addition to their antiinflammatory and antifibrotic action, idoxifene and E2 could enhance antioxidant and antiapoptotic activity in hepatic fibrosis in rats.