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 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: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Yukitaka
authors: Y
authors: Yoshikawa
authors: Taishi
authors: T
authors: Miyashita
authors: Satonori
authors: S
authors: Higuchi
authors: Koichi
authors: K
authors: Tsuneyama
authors: Shinya
authors: S
authors: Endo
authors: Tohru
authors: T
authors: Tsukui
authors: Yasuyuki
authors: Y
authors: Toyoda
authors: Tatsuki
authors: T
authors: Fukami
authors: Miki
authors: M
authors: Nakajima
authors: Tsuyoshi
authors: T
authors: Yokoi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D047628:Estrogen Receptor alpha / Q000819:agonists*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D004997:Ethinyl Estradiol; D020849:Raloxifene Hydrochloride