Interaction of fluoroethane chlorofluorocarbon (CFC) substitutes with microsomal cytochrome P450. Stimulation of P450 activity and chlorodifluoroethene metabolism.
The abilities of halothane and the fluoroethane chlorofluorocarbon (CFC) substitutes, FC-123, FC-133a, FC-124, FC-134a and FC-125, to stimulate cytochrome P450 activities and 2-chloro-1,1-difluoroethene (CDE) defluorination in hepatic microsomes from phenobarbital-treated rabbits were compared. At 1% (v/v) each, halothane and FC-123 similarly increased the consumption of NADPH and O2 by 300 and 100%, respectively, over 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 consumption by only 70 and 50%, respectively. No metabolism of any fluoroethane could be detected under the incubation conditions used. Halothane and FC-123 were most effective in stimulating CDE metabolism with increases 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 and FC-125 had no effect. While CDE metabolism was enhanced in the presence 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 consumption 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 and CDE metabolism is a function of their lipid solubility, and fluoroethane-enhanced CDE metabolism is related to the ability of these compounds to increase uncoupled P450 activity.
Wang
Y
Y
Department of Anesthesia, University of Iowa, Iowa City 52242.
Olson
M J
MJ
Baker
M T
MT
D000818:Animals; D017402:Chlorofluorocarbons / Q000494:pharmacology* / Q000633:toxicity; D064227:Chlorofluorocarbons, Ethane; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006221:Halothane / Q000031:analogs & derivatives* / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption; D010634:Phenobarbital; D011817:Rabbits; D012995:Solubility; D004980:Ethane / Q000031:analogs & derivatives; D005466:Fluorocarbons
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D003577:Cytochrome P-450 Enzyme System; D006221:Halothane; D006845:Hydrocarbons, Fluorinated; D009249:NADP; D010634:Phenobarbital; C067411:2,2-dichloro-1,1,1-trifluoroethane; C016800:1,1,1-trifluoro-2-chloroethane; C063006:norflurane; D004980:Ethane; D005466:Fluorocarbons; C068320:1,1-dichloro-1-fluoroethane