P450-DEPENDENT AND NONENZYMATIC HUMAN LIVER MICROSOMAL DEFLUORINATIONOF FLUOROMETHYL-2,2-DIFLUORO-1-(TRIFLUOROMETHYL)VINYL ETHER (COMPOUND-A), A SEVOFLURANE DEGRADATION PRODUCT

The volatile anesthetic sevoflurane is degraded by strong bases in the carbon dioxide absorbent in clinical anesthesia machines to fluoromet hyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, also called ''C ompound A''), FDVE is nephrotoxic in rats, where it is extensively bio transformed. Patients undergoing sevoflurane anesthesia have been expo sed to low inhaled concentrations of FDVE. Although sevoflurane renal toxicity under conditions of FDVE formation has not been reported, the re is still considerable concern about FDVE metabolism in humans and t he potential for FDVE nephrotoxicity. Sevoflurane undergoes P450-catal yzed liver microsomal defluorination. We tested the hypothesis that FD VE also undergoes human liver microsomal defluorination. Defluorinatio n occurred both in the absence and presence of NADPH; rates of total a nd NADPH-dependent fluoride formation were 1.6 +/- 0.1 and 1+/-0.1 nmo l min(-1). mg(-1) protein (mean +/- SD), respectively, in four human l ivers. Enzymatic defluorination was linear with respect to time, prote in concentration, and was saturable with respect to substrate concentr ation, NADPH-dependent, but not NADPH-independent, FDVE defluorination was partially inhibited by coumarin, orphenadrine, diethyldithiocarba mate, and 4-methypyrazole. Microsomes containing cDNA-expressed human P4502E1 exhibited substantial catalytic activity toward FDVE defluorin ation. Microsomal FDVE defluorination was significantly diminished in the presence of the parent anesthetic, sevoflurane, from 1.3 to 0.6 nm ol min(-1). mg(-1). These results show that FDVE undergoes both P450-c atalyzed and nonenzymatic defluorination by human liver microsomes, P4 502E1 is implicated in the enzymatic defluorination. Nonenzymatic defl uorination may result from FDVE addition to protein thiols. Enzymatic and/or nonenzymatic defluorination may be etiologic factors in FDVE ne phrotoxicity in rats, In contrast, P450-dependent FDVE defluorination may be of less clinical consequence in humans, because it is inhibited by the parent anesthetic, sevoflurane.