Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries.

Abstract

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia-reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs.

• Authors: Yukitaka Yoshikawa, Taishi Miyashita, Satonori Higuchi, Koichi Tsuneyama, Shinya Endo, Tohru Tsukui, Yasuyuki Toyoda, Tatsuki Fukami, Miki Nakajima, Tsuyoshi Yokoi
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 264 Issue 1 Pg. 42-50 (Oct 01 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22841776 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Estrogen Receptor alpha
• RNA, Messenger
• RNA, Small Interfering
• Selective Estrogen Receptor Modulators
• Tamoxifen
• Ethinyl Estradiol
• Raloxifene Hydrochloride

Topics

• Animals
• Cell Differentiation (drug effects)
• Chemical and Drug Induced Liver Injury (pathology, prevention & control)
• Estrogen Receptor alpha (agonists)
• Ethinyl Estradiol (pharmacology)
• Female
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (metabolism)
• RNA, Small Interfering (administration & dosage)
• Raloxifene Hydrochloride (pharmacology)
• Selective Estrogen Receptor Modulators (pharmacology)
• Tamoxifen (pharmacology)
• Up-Regulation (drug effects)