The toxicity of the anesthetic fluroxene (2,2,2-trifluorethyl vinyl ether) and its analogues is mediated by hepatic microsomal cytochromes P-450. The specific enzyme and its role in this toxicity will be investigated by using a variety of inducing agents to enhance the levels of different cytochromes P-450. The role of the microsomal metabolism of fluroxene in potentiating its hepatotoxicity will be investigated by utilization of a variety of chemical analogues. The possibility of generation of reactive intermediates will be tested with the bacterial system of Ames using a variety of differently induced microsomes. A correlation of a positive result in the Ames test with observations of hepatotoxicity under the same conditions, with the same fluroxene analogue, will be interpreted as a reactive intermediate being the source of the liver damage. The possibility that metabolism of fluoroxene results in the covalent binding of metabolites to cellular macromolecules will be investigated using 14C labeled anesthetic. The conditions leading to covalent binding will be correlated with conditions potentiating fluroxene toxicity to determine any relationship of toxicity to binding. BIBLIOGRAPHIC REFERENCES: Chiang, Y.L., Kaminsky, L.S. and King, T.E. 1976. A Complex of Cardiac Cytochrome c1 and Cytochrome c. J. Biol. Chem. 251:29-36. Harrison, G.G., Ivanetich, K.M., Kaminsky, L.S. and Halsey, M.J. 1976. Fluroxene Toxicity - A Chemical Aspect. Anesth. Analg. 55:529-533.
NIH ExPorter
NIH ExPorter