Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4

Objective: Halothane undergoes both oxidative and reductive metabolism by c ytochrome P-450 (CYP), respectively causing rare immune-mediated hepatic ne crosis 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 hum an CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mec hanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidati on 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 met abolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath , fluoride in urine, and oxidative metabolites trifluoroacetic acid and bro mide in urine were measured for 48 h postoperatively. Lipid peroxidation wa s assessed by plasma F-2-isoprostane concentrations. Results: The halothane dose was similar in all groups. Methoxsalen decrease d 0- to 8-h trifluoroacetic acid (23 +/- 20 mu mol vs 116 +/- 78 mu mol) an d bromide (17 +/- 11 mu mol vs 53 +/- 49 mu mol) excretion (P < 0.05), but not thereafter. Plasma F-2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither me thoxsalen nor troleandomycin diminished reductive halothane metabolite or F -2-isoprostane concentrations. Conclusions: These results provide the first evidence for halothane-depende nt 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 in hibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical ha lothane reduction and lipid peroxidation were not amenable to suppression b y CYP inhibitors.