title: Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.
abstract: OBJECTIVE
  Halothane undergoes both oxidative and reductive metabolism by cytochrome P450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism.
  
  
  METHODS
  Patients (n = 9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations.
  
  
  RESULTS
  The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 +/- 20 micromol vs 116 +/- 78 micromol) and bromide (17 +/- 11 micromol vs 53 +/- 49 micromol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations.
  
  
  CONCLUSIONS
  These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: D C
authors.initials: DC
authors.lastname: Hankins
authors.forename: K
authors.initials: K
authors.lastname: Fenstamaker
authors.forename: K
authors.initials: K
authors.lastname: Cox
mesh_terms: D000328:Adult; D000368:Aged; D018685:Anesthetics, Inhalation / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D001965:Bromides / Q000652:urine; D017402:Chlorofluorocarbons / Q000032:analysis; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015237:Dinoprost / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005459:Fluorides / Q000652:urine; D006221:Halothane / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014269:Trifluoroacetic Acid / Q000652:urine; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D001965:Bromides; D017402:Chlorofluorocarbons; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C016800:1,1,1-trifluoro-2-chloroethane; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D014217:Troleandomycin; D014269:Trifluoroacetic Acid; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C104464:CYP3A protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005459:Fluorides; C018483:2-chloro-1,1-difluoroethylene; D008730:Methoxsalen; D006221:Halothane