Reductive oxygenation of carbon tetrachloride: trichloromethylperoxyl radical as a possible intermediate in the conversion of carbon tetrachloride to electrophilic chlorine.
Under aerobic conditions, rat liver microsomes convert carbon tetrachloride to an electrophilic form of chlorine that is trapped with 2,6-dimethylphenol to form 4-chloro-2,6-dimethylphenol. The mechanism of cytochrome P-450-catalyzed electrophilic chlorine formation from carbon tetrachloride was examined with structure-activity studies of electrophilic halogen formation and chemical and in vitro microsomal studies. 4-Chloro-2,6-dimethylphenol is not formed as a consequence of a reaction of 2,6-dimethylphenoxyl radical with carbon tetrachloride or carbon tetrachloride-induced lipid peroxyl radical formation. Only tetrahalomethanes were found to yield electrophilic halogens. The chemical oxidants hydrogen peroxide, cumene hydropheroxide, sodium periodate, and iodobenzene diacetate did not support electrophilic halogen formation from carbon tetrachloride, carbon tetrabromide, or hexachloroethane in microsomal studies. The addition of superoxide dismutase, catalase, sodium azide, or glutathione to microsomal incubations did not affect the rate of electrophilic chlorine formation, whereas Paraquat completely inhibited the reaction. The radical spin trap phenyl t-butyl nitrone (14 mM) completely inhibited electrophilic chlorine formation. The rate of electrophilic chlorine formation was highest at 2-5% atmospheric oxygen, whereas anaerobiosis completely inhibited electrophilic chlorine formation, and high oxygen tension impaired electrophilic chlorine formation. These results preclude direct oxidation of carbon tetrachloride or a reaction of superoxide anion radical with carbon tetrachloride as the initial step in electrophilic chlorine formation and suggest that the likely initial step is reductive dehalogenation of carbon tetrachloride to trichloromethyl radical which then traps oxygen to form trichloromethylperoxyl radical. Subsequent reaction of trichloromethyl peroxyl radical leads to electrophilic chlorine. These findings may have important implications concerning carbon tetrachloride-induced lipid peroxidation and carbon tetrachloride hepatotoxicity.
D000332:Aerobiosis; D000818:Animals; D002251:Carbon Tetrachloride / Q000378:metabolism*; D002713:Chlorine / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006846:Hydrocarbons, Halogenated / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D006846:Hydrocarbons, Halogenated; D002713:Chlorine; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride