P450-DEPENDENT AND NONENZYMATIC HUMAN LIVER MICROSOMAL DEFLUORINATIONOF FLUOROMETHYL-2,2-DIFLUORO-1-(TRIFLUOROMETHYL)VINYL ETHER (COMPOUND-A), A SEVOFLURANE DEGRADATION PRODUCT
Ed. Kharasch et Dc. Hankins, P450-DEPENDENT AND NONENZYMATIC HUMAN LIVER MICROSOMAL DEFLUORINATIONOF FLUOROMETHYL-2,2-DIFLUORO-1-(TRIFLUOROMETHYL)VINYL ETHER (COMPOUND-A), A SEVOFLURANE DEGRADATION PRODUCT, Drug metabolism and disposition, 24(6), 1996, pp. 649-654
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.