Role of 5-HT degradation in acute liver injury induced by carbon tetrachloride

5-hydroxytryptamine (5-HT) is involved in the pathological processes of several liver diseases. Acute liver injury underlies the development of many liver diseases, but the mechanism remains unclear. We aimed to investigate the role of 5-HT in carbon tetrachloride (CCl₄)-induced acute liver injury. Acute liver injury was induced with CCl₄ (10 mg/kg) in mice pretreated with the 5-HT_2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP). LO2 cells were treated with CCl₄, 5-HT or 2,5-dimethoxy-4-idopametamine and pretreated with SH, CDP or the monoamine oxidase A (MAO-A) inhibitor clorgyline. Hematoxylin-eosin staining, immunohistochemistry, Real-time quantitative PCR, western blotting, fluorescent probe and biochemical markers were used to evaluate liver compromise. 5-HT_2A receptor, 5-HT synthetase and MAO-A were expressed in hepatocytes; their gene and protein expression were upregulated by CCl₄, which led to the degradation of mitochondrial 5-HT and overproduction of reactive oxygen species (ROS). Hepatic injury may be aggravated by ROS, which induce oxidative stress and the phosphorylation of p38 mitogen-activated protein kinase, Jun N-terminal kinase, extracellular regulated protein kinase, signal transducer and activator of transcription 3 and nuclear factor kappa-B. 5-HT_2A receptor may contribute to acute liver injury by modulating 5-HT synthase and MAO-A expression. The synergistic action of SH and CDP treatment may inhibit CCl₄-induced acute liver injury in a dose-dependent manner. Hence, CCl₄-induced acute liver injury is due to an increase in mitochondrial ROS production caused by increased 5-HT degradation and probably involves increases in 5-HT_2A receptor expression and 5-HT synthesis.