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

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• 作者：Yukitaka Yoshikawa ; Taishi Miyashita ; Satonori Higuchi ; Koichi Tsuneyama ; Shinya Endo ; Tohru Tsukui ; Yasuyuki Toyoda ; Tatsuki Fukami ; Miki Nakajima ; Tsuyoshi Yokoi
• 关键词：Monocyte to macrophage differentiation-associated 2 (Mmd2) ; Estrogen receptor ¦Á ; Species differences ; Drug-induced liver injury ; Chemical-induced liver injury
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 出版时间：1 October, 2012
• 年：2012
• 卷：264
• 期：1
• 页码：42-50
• 全文大小：1069 K

文摘

Although estrogen receptor (ER)¦Á 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 ER¦Á have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ER¦Á 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 ER¦Á-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 ER¦Á 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.