Many halogenated inhalational anesthetics have been associated with proven toxic reactions which occurs as a results of the metabolism of these halogenated compounds. Recent studies of halothane in this laboratory indicate that a metabolite of it binds irreversibly to phospholipids in liver under conditions of low oxygen. Another metabolite binds to protein. We plan to pursue the nature of the binding to phosphoslipids and to determine if nutritional factors play a role in this binding. Since halothane hepatitis has been produced in rats in our laboratory, the effects of the dietary factors can also be determined on the development of this toxicity. We plan to continue the studies to determine if the metabolite which binds to protein does so to a specific protein. We also plan to determine if the binding to phospholipids may be a protective mechanism and in the absence of this binding if there might be an increase in binding to protein. Using the halothane hepatitis model in rats, we plan to continue our study of a plasma factor which appear to play a role in the process of cell injury. This model for cell injury in chemically induced hepatitis also requires lymphocytes isolated from chemically damaged animals and also a liver lipoprotein or isolated hepatocytes. By following the levels of ornithine decarboxylase, an enzyme which normally is in very low concentration except in developing or damaged tissue, we plan to determine the effects of the volatile anesthetics on this enzyme in various organs in the adult animal will special emphasis on the liver. We also propose to study the effects of neonatal or maternal anesthetic administration on ornithine decarboxylase activity in brain and heart of developing rats. The proposed studies will include in vitro incubation, isolated hepatocytes, isolated perfused organs as well as some in vivo preparations. Associated with this halothane hepatoxicity is a loss of cytochrome P-450. Studies are underway to determine if there is a loss of a specific cytochrome P-450.
NIH ExPorter
NIH ExPorter