Acute stimulation of trifluoroethene defluorination and cytochrome P450 inactivation in the rat by exposure to isoflurane.
The effect of isoflurane on trifluoroethene (TFE) defluorination and cytochrome P450 inactivation was examined in rats to determine the influence of this anesthetic on in vivo fluoroethene metabolism. Exposure of rats to TFE (0.5%, v/v) or a mixture of TFE and isoflurane (0.5% each) in oxygen for 60 min resulted in plasma fluoride increased over that in nonexposed or isoflurane (0.5%)-exposed animals. In untreated rats plasma fluoride levels following TFE and TFE-isoflurane exposures were approximately equal. In rats treated with phenobarbital, however, isoflurane increased plasma fluoride over two times that in rats exposed to TFE alone. Likewise cytochrome P450 levels declined 24% in TFE-exposed animals and 64% in rats exposed to TFE-isoflurane. The ability of microsomes from fluorocarbon-exposed animals to metabolize (R)- and (S)-warfarin indicates that TFE exposure inactivated the phenobarbital-inducible isozymes P450IIB1, P450IIC6, and P450IIIA to approximately equal degrees (21-35%). TFE-isoflurane exposure further inhibited P450IIB1 and PB450IIC6 to 50-70%, but had only a minor effect on P450IIIA activity. These data demonstrate that the defluorination of TFE in vivo by the phenobarbital-inducible cytochrome P450 isozymes is increased by isoflurane, and that isoflurane enhances the ability of TFE to inactivate cytochromes P450 in an isozyme-selective manner.
Baker
M T
MT
Department of Anesthesia, University of Iowa, Iowa City 52242.
Ronnenberg
W C
WC
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005459:Fluorides / Q000097:blood; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism*; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010634:Phenobarbital; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D007530:Isoflurane; D005459:Fluorides; D010634:Phenobarbital; C074585:trifluoroethene