Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-y

• 来源期刊: 中国药理学报（英文版）
• 关键词: idiosyncratic drug-induced liver injury Polygonum multiflorum Thunb cis-stilbene glucoside LPS PPAR-γ NF-KB pioglitazone
• 年，卷（期）: 2017,（10）
• 页码范围: 1340-1352
• 页数: 13页
• 语种: 英文
• DOI: 10.1038/aps.2017.32

摘要

The root of Polygonum multiflorum Thunb (PM) has been used in China to treat a variety of diseases,such as constipation,early graying of the hair and hyperlipemia.Recent evidence shows that PM causes idiosyncratic drug-induced liver injury (IDILI) in humans.In this study,we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non-hepatotoxic dose of LPS.SD rats were orally administered 3 potentially hepatotoxic compounds of PM:cis-stilbene glucoside (cis-SG,50 mg/kg),trans-SG (50 mg/kg) or emodin (5 mg/kg),followed by injection of LPS (2.8 mg/kg,iv).Serum and liver histology were evaluated 7 h after LPS injection.Among the 3 compounds tested,cis-SG,but not emodin or trans-SG,induced severe liver injury in rats when combined with LPS.The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated.The liver tissues showed increased injury,hepatocyte apoptosis,and macrophage infiltration,and decreased cell proliferation.Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-γ (PPAR-γ) and LPS/cis-SG-induced liver injury.Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-γ pathway in the liver tissues of LPS/cis-SG-treated rats.Pre-treatment with a PPAR-y agonist pioglitazone (500 g/kg,ig) reversed LPS/ cis-SG-induced liver injury,which was associated with inhibiting the nuclear factor kappa B (NF-κB) pathway.These data demonstrate that cis-stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-γ in a rat model of IDILI.