title: Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice.
abstract: 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 24h. 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) α 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.
authors.affiliation: University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030, USA. adarsh.gandhi@nih.gov
authors.forename: Adarsh
authors.initials: A
authors.lastname: Gandhi
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Pranav
authors.initials: P
authors.lastname: Shah
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.forename: Romi
authors.initials: R
authors.lastname: Ghose
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002746:Chlorpromazine / Q000633:toxicity*; D006651:Histocytochemistry; D015151:Immunoblotting; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013682:Teichoic Acids / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D013682:Teichoic Acids; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D002746:Chlorpromazine