The intent of this study is to determine the molecular basis of halothane- induced hepatotoxicity, a disease that is often fatal in humans. This toxicity has been thought to have an immunological basis because in over 80% of the reported cases, it occurs in individuals who have received halothane on a previous occasion. Although no one has yet shown that patients recovering from halothane-induced hepatotoxicity are sensitized to their own hepatocytes, studies have indicated that this may actually occur. Results suggest that halothane is metabolized to a product that reacts covalently with the external surface of hepatocytes. In susceptible individuals, these altered hepatocyte membranes may be immunogenic and on further exposure to halothane, a hypersensitivity reaction may ensue. Based upon metabolic findings, we feel that the most likely way that halothane can initiate an immune response is for its acyl haline metabolite to react covalently with hepatocyte plasma membranes and alter their antigenicity. In sensitive individuals, an immune response would be initiated and upon second exposure to halothane hepatocellular damage might occur. To test this idea we have developed immuno-chemical methods to detect and measure trifluoracetylated hepatocyte plasma membranes and antibodies that have been directed against these modified membranes. Our findings could serve as a model study for investigating other drug-induced toxicities which are believed to have an immunological basis.
