Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, USA.
Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, USA.
Biol Chem. 2018 Oct 25;399(11):1237-1248. doi: 10.1515/hsz-2017-0324.
Occupational and environmental exposures to industrial chemicals are known to cause hepatotoxicity and liver injury, in humans and in animal models. Historically, research has focused on severe acute liver injury (e.g. fulminant liver failure) or endstage diseases (e.g. cirrhosis and HCC). However, it has become recently recognized that toxicants can cause more subtle changes to the liver. For example, toxicant-associated steatohepatitis, characterized by hepatic steatosis, and inflammation, was recently recognized in an occupational cohort exposed to vinyl chloride. At high occupational levels, toxicants are sufficient to cause liver damage and disease even in healthy subjects with no comorbidities for liver injury. However, it is still largely unknown how exposure to toxicants initiate and possibly more importantly exacerbate liver disease, when combined with other factors, such as underlying non-alcoholic fatty liver disease caused by poor diet and/or obesity. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease, rational targeted therapy can be developed to better predict risk, as well as to treat or prevent this disease. The purpose of this review is to summarize established and proposed mechanisms of volatile organic compound-induced liver injury and to highlight key signaling events known or hypothesized to mediate these effects.
职业和环境暴露于工业化学品已知可导致人类和动物模型的肝毒性和肝损伤。从历史上看，研究主要集中在严重的急性肝损伤（例如暴发性肝衰竭）或终末期疾病（例如肝硬化和 HCC）上。然而，最近人们已经认识到，毒物会对肝脏造成更微妙的变化。例如，在接触氯乙烯的职业队列中，最近发现与毒物相关的脂肪性肝炎，其特征是肝脂肪变性和炎症。在高职业水平下，即使对于没有肝损伤合并症的健康受试者，毒物也足以导致肝损伤和疾病。然而，当与其他因素（例如由不良饮食和/或肥胖引起的非酒精性脂肪肝疾病）结合时，毒物如何引发并可能更重要的是加剧肝病，目前仍在很大程度上未知。通过更好地了解介导毒物诱导的肝病发生和进展的机制和危险因素，可以开发合理的靶向治疗方法，以更好地预测风险，以及治疗或预防这种疾病。本文综述的目的是总结挥发性有机化合物诱导的肝损伤的既定和提出的机制，并强调已知或假设介导这些作用的关键信号事件。
