Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

详细信息    查看全文

• 作者：Adarsh Gandhi^a ; ¹ ; ^{adarsh.gandhi@nih.gov} ; Tao Guo^a ; ² ; ^{tguo4@jhu.edu} ; Pranav Shah^a ; ¹ ; Bhagavatula Moorthy^b ; Romi Ghose^a ; ^{rghose@uh.edu}
• 关键词：CPZ ; chlorpromazine ; IADRs ; idiosyncratic adverse drug reactions ; JNK ; c-Jun-N-terminal kinase ; LPS ; lipopolysaccharide ; LTA ; lipoteichoic acid ; TIRAP ; Toll-interleukin 1 receptor domain containing adaptor protein ; TLR ; Toll-like receptor ; TNF ; tumor necr
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：266
• 期：3
• 页码：430-438
• 全文大小：1365 K

文摘

Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP^+/+ and TIRAP^?/? mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ~ 3-4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) ¦Á and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP^+/+ mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP^?/? mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs.