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Title: 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 amore » 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. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression via ERα.« less

Authors:
; ;  [1];  [2];  [1];  [3]; ; ;  [1];  [1]
  1. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)
  2. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan)
  3. Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan)
Publication Date:
OSTI Identifier:
22215923
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 264; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DNA; DRUGS; ESTRADIOL; INJURIES; KNOCK-OUT REACTIONS; LIVER; MACROPHAGES; MESSENGER-RNA; MICE; MONOCYTES; RECEPTORS; TAMOXIFEN

Citation Formats

Yoshikawa, Yukitaka, Miyashita, Taishi, Higuchi, Satonori, Tsuneyama, Koichi, Endo, Shinya, Tsukui, Tohru, Toyoda, Yasuyuki, Fukami, Tatsuki, Nakajima, Miki, and Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.06.023.
Yoshikawa, Yukitaka, Miyashita, Taishi, Higuchi, Satonori, Tsuneyama, Koichi, Endo, Shinya, Tsukui, Tohru, Toyoda, Yasuyuki, Fukami, Tatsuki, Nakajima, Miki, & Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries. United States. doi:10.1016/J.TAAP.2012.06.023.
Yoshikawa, Yukitaka, Miyashita, Taishi, Higuchi, Satonori, Tsuneyama, Koichi, Endo, Shinya, Tsukui, Tohru, Toyoda, Yasuyuki, Fukami, Tatsuki, Nakajima, Miki, and Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp. Mon . "Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries". United States. doi:10.1016/J.TAAP.2012.06.023.
@article{osti_22215923,
title = {Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries},
author = {Yoshikawa, Yukitaka and Miyashita, Taishi and Higuchi, Satonori and Tsuneyama, Koichi and Endo, Shinya and Tsukui, Tohru and Toyoda, Yasuyuki and Fukami, Tatsuki and Nakajima, Miki and Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp},
abstractNote = {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. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression via ERα.},
doi = {10.1016/J.TAAP.2012.06.023},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 264,
place = {United States},
year = {Mon Oct 01 00:00:00 EDT 2012},
month = {Mon Oct 01 00:00:00 EDT 2012}
}