Clinical enflurane metabolism by cytochrome P450 2E1.
BACKGROUND
Fluorinated ether anesthetic hepatotoxicity and nephrotoxicity are mediated by cytochrome P450-catalyzed oxidative metabolism. Metabolism of the volatile anesthetic enflurane to inorganic fluoride ion by human liver microsomes in vitro is catalyzed predominantly by the cytochrome P450 isoform CYP2E1. This investigation tested the hypothesis that P450 2E1 is also the isoform responsible for human enflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1.


METHODS
Twenty patients undergoing elective surgery were randomized to receive disulfiram (500 mg orally; n = 10) or nothing (control subjects; n = 10) the evening before surgery. All patients received a standard anesthetic of enflurane (2.2% end-tidal) in oxygen for 3 hours. Blood enflurane concentrations were measured by gas chromatography. Plasma and urine fluoride concentrations were quantitated by ion-selective electrode.


RESULTS
Patient groups were similar with respect to age, weight, gender, duration of surgery, and blood loss. Total enflurane dose, measured by cumulative end-tidal enflurane concentrations (3.9 to 4.1 MAC-hr) and by blood enflurane concentrations, was similar in both groups. Plasma fluoride concentrations increased from 3.6 +/- 1.5 mumol/L (baseline) to 24.3 +/- 3.8 mumol/L (peak) in untreated patients (mean +/- SE). Disulfiram treatment completely abolished the rise in plasma fluoride concentration. Urine fluoride excretion was similarly significantly diminished in disulfiram-treated patients. Fluoride excretion in disulfiram-treated patients was 62 +/- 10 and 61 +/- 12 mumol on days 1 and 2, respectively, compared with 1090 +/- 180 and 1200 +/- 220 mumol in control subjects (p < 0.05 on each day).


CONCLUSIONS
Disulfiram prevented fluoride ion production after enflurane anesthesia. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical enflurane metabolism in vivo.
Kharasch
E D
ED
Department of Anesthesiology, University of Washington, Seattle 98195.
Thummel
K E
KE
Mautz
D
D
Bosse
S
S
D000328:Adult; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology*; D004737:Enflurane / Q000097:blood / Q000378:metabolism* / Q000652:urine; D005260:Female; D005459:Fluorides / Q000097:blood / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004737:Enflurane; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D005459:Fluorides; D004221:Disulfiram