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

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.taap.2012.06.023

Cited by 17 publications

(14 citation statements)

References 30 publications

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“…TAM is a SERM that can act as an estrogen agonist in the liver (Obsorne and Fuqua, 1994). We previously reported that TAM has a hepatoprotective effects against various drug-induced and chemical-induced acute liver injuries (Yoshikawa et al, 2012). However, there is little information about the effects of TAM on steatosis and NASH.…”

Section: Discussionmentioning

confidence: 99%

“…TAM (1 mg/kg) dissolved in saline was intraperitoneally administered for 5 consecutive days. We previously reported that administration of TAM for 5 days demonstrated hepatoprotective effects against chemical-induced acute liver injuries (Yoshikawa et al, 2012). Twelve hours after the final administration of TAM, the mice were sacrificed.…”

Section: Animal Treatmentsmentioning

confidence: 99%

“…TAM acts as an antagonist in the mammary gland, but acts as an agonist in the uterus, bone tissue, and liver (Obsorne and Fuqua, 1994;Mitlak and Cohen, 1997;Cosman and Lindsay, 1999). We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries (Yoshikawa et al, 2012). However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed.…”

Section: Introductionmentioning

confidence: 99%

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Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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-Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Animal Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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“…Another report found that tamoxifen played a hepatoprotective role against hepatotoxic compounds via hepatic induction of monocyte to macrophage differentiation-associated 2 (Mmd2) in an ERa dependent manner [35]. Finally, in female WSB/EiJ mice, tamoxifen treatment upregulated two key regulators of hepatic fatty acid b-oxidation, namely lipocalin 13 (Lcn13) and the peroxisome proliferatoractivated receptor gamma (PPARg) [36].…”

Section: Study Subjectsmentioning

confidence: 99%

Effect of selective estrogen receptor modulators on metabolic homeostasis

Lovre

Mauvais-Jarvis

2016

Biochimie

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“…For estrogen-induced intrahepatic cholestasis, mice received subcutaneous injections of EE2 (10 mg/kg) or vehicle (olive oil) daily for 5 days (Yamamoto et al, 2006). For the activation of ERa alone (without cholestasis), mice received intraperitoneal injections of EE2 (5 mg/kg) or vehicle daily for 5 days (Yoshikawa et al, 2012). Mice were sacrificed on the sixth day (i.e., 24 hours after the last dose), and blood and liver tissues were collected.…”

Section: Methodsmentioning

confidence: 99%

Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice

Pan

Jeong

2015

Mol Pharmacol

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Cholestasis activates bile acid receptor farnesoid X receptor (FXR) and subsequently enhances hepatic expression of small heterodimer partner (SHP). We previously demonstrated that SHP represses the transactivation of cytochrome P450 2D6 (CYP2D6) promoter by hepatocyte nuclear factor (HNF) 4a. In this study, we investigated the effects of estrogeninduced cholestasis on CYP2D6 expression. Estrogen-induced cholestasis occurs in subjects receiving estrogen for contraception or hormone replacement, or in susceptible women during pregnancy. In CYP2D6-humanized transgenic (Tg-CYP2D6) mice, cholestasis triggered by administration of 17a-ethinylestradiol (EE2) at a high dose led to 2-to 3-fold decreases in CYP2D6 expression. This was accompanied by increased hepatic SHP expression and subsequent decreases in the recruitment of HNF4a to CYP2D6 promoter. Interestingly, estrogen-induced cholestasis also led to increased recruitment of estrogen receptor (ER) a, but not that of FXR, to Shp promoter, suggesting a predominant role of ERa in transcriptional regulation of SHP in estrogen-induced cholestasis. EE2 at a low dose (that does not cause cholestasis) also increased SHP (by ∼50%) and decreased CYP2D6 expression (by 1.5-fold) in Tg-CYP2D6 mice, the magnitude of differences being much smaller than that shown in EE2-induced cholestasis. Taken together, our data indicate that EE2-induced cholestasis increases SHP and represses CYP2D6 expression in Tg-CYP2D6 mice in part through ERa transactivation of Shp promoter.

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

Cited by 17 publications

References 30 publications

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Effect of selective estrogen receptor modulators on metabolic homeostasis

Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice

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