Abstract
α-Naphthylisothiocyanate (ANIT) has been used extensively as a model cholestatic agent. Its acute toxicity in animals is characterized by neutrophilic inflammation, mild periportal hepatocellular necrosis, and more pronounced injury to intrahepatic bile ducts. Following repeated administration, ANIT causes bile duct hyperplasia and biliary cirrhosis. Although the role of oxidative metabolism in ANIT hepatotoxicity remains unclear, ANIT conjugates bind reversibly to glutathione (GSH) in hepatocytes. The GSH S-conjugate is transported by multidrug resistance-associated protein 2 into bile, where it concentrates and dissociates, exposing bile duct epithelial (BDE) cells to large concentrations of ANIT. In response, BDE cells produce chemokines that attract neutrophils, the activation of which leads to hepatocellular injury. Accumulation of bile acids and other biliary constituents in the liver may be involved in injury. The hemostatic system also plays a role in the progression to liver injury. Although ANIT continues to be a useful agent for the study of BDE cell injury and its consequences, much remains unknown about the molecular mechanisms by which ANIT toxicity occurs.
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