Isoflurane acts as an inhibitor of oxidative dehalogenation while acting as an accelerator of reductive dehalogenation of halothane in guinea pig liver microsomes

• Published in: Toxicology (Amsterdam) Vol. 104; no. 1; pp. 123 - 128
• Main Author: Fujii, Kohyu
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 15.12.1995; Amsterdam Elsevier Science
• Subjects: Anesthetics, Inhalation - administration & dosage; Anesthetics, Inhalation - metabolism; Anesthetics, Inhalation - toxicity; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Chlorofluorocarbons - metabolism; Cytochrome P-450 Enzyme System - metabolism; Enhancement; Guinea Pigs; Halothane; Halothane - analogs & derivatives; Halothane - metabolism; Inhibition; Interaction; Isoflurane; Isoflurane - administration & dosage; Isoflurane - toxicity; Male; Medical sciences; Metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; NADPH-Ferrihemoprotein Reductase; Neuropharmacology; Oxidation-Reduction; Oxidoreductases - metabolism; Pharmacology. Drug treatments; Spectrophotometry, Ultraviolet; Trifluoroacetic Acid - metabolism; Inhibition; Metabolism; Enhancement; Interaction; Isoflurane; Halothane; Volatile compound; Metabolite; Cytochrome P450; Liver; Rodentia; Microsome; In vitro; Local anesthetic; Vertebrata; Mammalia; Guinea pig; Animal; Drug interaction; Mechanism of action
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/0300-483X(95)03154-8

The effects of isoflurane, 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether, on the oxidative metabolism of halothane to produce trifluoroacetic acid (TFA) and on the reductive metabolism of halothane to produce chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) in liver microsomes of guinea pig were examined. Isoflurane enhanced the production of CDE and CTE and inhibited the production of TFA. Isoflurane enhanced cytochrome P450 reduction and formation of an intermediate complex with cytochrome P450 without enhancement of NADPH-cytochrome P450 reductase (EC 1.6.2.4) activity. We conclude that isoflurane interacts with cytochrome P450 to prevent the formation of the halothane-cytochrome P450 complex, causing inhibition of the oxidative dehalogenation. This interaction of isoflurane enhances the reduction of cytochrome P450 and the formation of a reductive intermediate-cytochrome P450 complex under anaerobic conditions causing reductive dehalogenation of halothane.