The overall aim of this investigation is to determine the manner in which microsomal metabolism of clinically used, volatile, fluorinated ether, anesthetics contributes to their potential toxicity. Studies will be performed with rats and mice in vivo, and rat, mouse and human tissue in vitro. Studies will continue with the anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) and its ethyl and allyl analogs and will be initiated with the recently introduced anesthetics sevoflurane (fluoromethyl 2, 2, 2-trifluoro-1- trifluoromethyl -ethyl ether) and isoflurane (1-chloro-2,2,2-trifluoro-ethyl difluoromethyl ether).
Specific aims are: (1) To determine the metabolic pathways of these anesthetics using in vitro microsomal and a variety of reconstituted purified cytochrome P-450 isozyme systems, and by molecular orbital calculations, and to compare metabolism by variously-induced rat and human hepatic microsomal and purified isozyme systems; by rat renal, hepatic and pulmonary microsomes to gain insight into anesthetic substrate specificity differences of the cytochromes P-450 from different organs; and by oxidative and reductive pathways. The ability of the various anesthetics to affect the suicide inactivation of cytochromes P-450 will be investigated. (2) To determine the toxicity of the anesthetics following administration to untreated or variously-induced rats. Rates of exhalation and blood concentrations of anesthetics and metabolites will be determined. Toxicity will be assessed by observations of lethality, clinical symptoms, histopathology, SGPT activities, kidney p-aminohippuric acid uptake, destruction of cytochrome P-450, and the potential of anesthetics and metabolites to produce immune dysfunction. The Ames test will be used to make in vitro assessments of the mutagenic potential of the anesthetic agents. (3) To determine the role of Ah locus gene products including cytochromes P-450, in mediating the toxicity of anesthetics in Beta-naphthoflavone induced mice. Ah responsive and non-responsive mice will be used. These studies will provide insight into the relationship between biotransformation and toxicity of anesthetics as an assessment of their safety, and for the design of better and more safe anesthetics. Comparisons of the data from rat and human hepatic tissue will provide a basis for assessing the potential toxicity of the anesthetic agents to humans, and to drug-anesthetic and environmental pollutant-anesthetic interactions.
