|show drug details|
|4-01-00-00156 (Beilstein Handbook Reference)|
|Ethane, 2-bromo-2-chloro-1,1,1-trifluoro-, (+-)-|
|Ethane, 2-bromo-2-chloro-1,1,1-trifluoro-, (R)-|
|Halothane [Anaesthetics, volatile]|
|Narcotann NE-spofa [Russian]|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.. E D Kharasch; D C Hankins; K Fenstamaker; K Cox (2000) European journal of clinical pharmacology display 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.
Concordance between trifluoroacetic acid and hepatic protein trifluoroacetylation after disulfiram inhibition of halothane metabolism in rats.. D K Spracklin; M E Emery; K E Thummel; E D Kharasch (2003) Acta anaesthesiologica Scandinavica display abstract
BACKGROUND: Cytochrome P4502E1(CYP2E1)-mediated oxidation of halothane to a reactive intermediate (trifluoroacyl chloride) that covalently binds to hepatic proteins forming trifluoroacetylated neoantigens is believed to be the initiating event in a complex immunologic cascade culminating in antibody formation and severe hepatic necrosis ('halothane hepatitis') in susceptible patients. Trifluoroacyl chloride may also hydrolyze to the stable metabolite trifluoroacetic acid (TFA). CYP2E1 inactivation by disulfiram or its primary metabolite, diethyldithiocarbamate, inhibits human halothane oxidation to TFA in vitro and in vivo. Nevertheless, disulfiram effects on hepatic protein trifluoroacetylation by halothane in vivo are unknown. This investigation tested the hypotheses that disulfiram prevents halothane-dependent protein trifluoroacetylation in vivo, and that TFA represents a biomarker for hepatic protein trifluoroacetylation. METHODS: Rats were pretreated with isoniazid (CYP2E1 induction), isoniazid followed by disulfiram (CYP2E1 inhibition), or nothing (controls), then anesthetized with halothane or nothing (controls). Plasma and urine TFA were quantified by ion HPLC; hepatic microsomal TFA-proteins were analyzed by Western blot. RESULTS: CYP2E1 induction increased both TFA and TFA-protein formation compared with uninduced halothane-treated rats. Disulfiram, even after CYP2E1 induction, nearly abolished both TFA and TFA-protein formation. Pretreatments similarly affected both TFA and TFA-protein formation across all groups. CONCLUSIONS: Disulfiram inhibition of CYP2E1-mediated halothane oxidation prevents hepatic protein trifluoroacetylation. Based on the concordance between TFA and TFA-protein formation, TFA appears to be a valid biomarker for TFA-protein formation. Disulfiram inhibition of human halothane oxidation in vivo, previously assessed by diminished TFA formation, probably also confers inhibition of hepatic TFA-protein formation.
Human reductive halothane metabolism in vitro is catalyzed by cytochrome P450 2A6 and 3A4.. D K Spracklin; K E Thummel; E D Kharasch (1996) Drug metabolism and disposition: the biological fate of chemicals display abstract
The anesthetic halothane undergoes extensive oxidative and reductive biotransformation, resulting in metabolites that cause hepatotoxicity. Halothane is reduced anaerobically by cytochrome P450 (P450) to the volatile metabolites 2-chloro-1,1-difluoroethene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE). The purpose of this investigation was to identify the human P450 isoform(s) responsible for reductive halothane metabolism. CDE and CTE formation from halothane metabolism by human liver microsomes was determined by GC/MS analysis. Halothane metabolism to CDE and CTE under reductive conditions was completely inhibited by carbon monoxide, which implicates exclusively P450 in this reaction. Eadie-Hofstee plots of both CDE and CTE formation were nonlinear, suggesting multiple P450 isoform involvement. Microsomal CDE and CTE formation were each inhibited 40-50% by P450 2A6-selective inhibitors (coumarin and 8-methoxypsoralen) and 55-60% by P450 3A4-selective inhibitors (ketoconazole and troleandomycin). P450 1A-, 2B6-, 2C9/10-, and 2D6-selective inhibitors (7,8-benzoflavone, furafylline, orphenadrine, sulfaphenazole, and quinidine) had no significant effect on reductive halothane metabolism. Measurement of product formation catalyzed by a panel of cDNA-expressed P450 isoforms revealed that maximal rates of CDE formation occurred with P450 2A6, followed by P450 3A4. P450 3A4 was the most effective catalyst of CTE formation. Among a panel of 11 different human livers, there were significant linear correlations between the rate of CDE formation and both 2A6 activity (r = 0.64, p < 0.04) and 3A4 activity (r = 0.64, p < 0.03). Similarly, there were significant linear correlations between CTE formation and both 2A6 activity (r = 0.55, p < 0.08) and 3A4 activity (r = 0.77, p < 0.005). The P450 2E1 inhibitors 4-methylpyrazole and diethyldithiocarbamate inhibited CDE and CTE formation by 20-45% and 40-50%, respectively; however, cDNA-expressed P450 2E1 did not catalyze significant amounts of CDE or CTE production, and microsomal metabolite formation was not correlated with P450 2E1 activity. This investigation demonstrated that human liver microsomal reductive halothane metabolism is catalyzed predominantly by P450 2A6 and 3A4. This isoform selectivity for anaerobic halothane metabolism contrasts with that for oxidative human halothane metabolism, which is catalyzed predominantly by P450 2E1.