INTERACTION OF FLUOROETHANE CHLOROFLUOROCARBON (CFC) SUBSTITUTES WITHMICROSOMAL CYTOCHROME-P450 - STIMULATION OF P450 ACTIVITY AND CHLORODIFLUOROETHENE METABOLISM

The abilities of halothane and the fluoroethane chlorofluorocarbon (CF C) substitutes, FC-123, FC-133a, FC-124, FC-134a and FC-125, to stimul ate cytochrome P450 activities and 2-chloro-1,1-difluoroethene (CDE) d efluorination in hepatic microsomes from phenobarbital-treated rabbits were compared. At 1% (v/v) each, halothane and FC-123 similarly incre ased the consumption of NADPH and 02 by 300 and 100%, respectively, ov er that in microsomes without substrate. FC-133a and FC-124 were less effective, increasing NADPH and O2 consumption by 150-200 and 70%. FC- 134a and FC-125 were the least effective, increasing NADPH and O2 cons umption by only 70 and 50%, respectively. No metabolism of any fluoroe thane could be detected under the incubation conditions used. Halothan e and FC-123 were most effective in stimulating CDE metabolism with in creases of CDE defluorination ranging from 1.5- to 2-fold. FC-133a and FC-124 enhanced CDE oxidation 89 and 74%, respectively, and FC-134a a nd FC-125 had no effect. While CDE metabolism was enhanced in the pres ence of the fluoroethanes, no additional NADPH or O2 was consumed when halothane or FC-124 was incubated with CDE compared with incubations containing only halothane or FC-124. Log-log plots of NADPH consumptio n and CDE metabolism with the olive oil/gas partition coefficients of each fluoroethane showed linear relationships. These data demonstrate that the activity of the fluoroethanes in stimulating P450 activity an d CDE metabolism is a function of their lipid solubility, and fluoroet hane-enhanced CDE metabolism is related to the ability of these compou nds to increase uncoupled P450 activity.