Metabolism of the chlorofluorocarbon substitute 1,1-dichloro-2,2,2-trifluoroethane by rat and human liver microsomes: the role of cytochrome P450 2E1.
1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons. The atmospheric lifetime of HCFC-123 is expected to be much shorter than those of chlorofluorocarbons; however, due to its lower stability and the presence of carbon-hydrogen bonds, metabolism of HCFC-123 in mammals and metabolism-dependent toxicity is likely. We compared the metabolism of HCFC-123 and its analog halothane in rat and human liver microsomes. 19F-NMR studies showed that trifluoroacetic acid is a major metabolite of HCFC-123. Besides trifluoroacetic acid, chlorodifluoroacetic acid and inorganic fluoride were identified as products of the enzymatic oxidation of HCFC-123 in rat and human liver microsomes by 19F-NMR and mass spectrometry. The metabolites were not detected in incubations with halothane. HCFC-123 and halothane were transformed by liver microsomes from untreated rats at low rates. Microsomes from ethanol-and pyridine-treated rats metabolized both HCFC-123 and halothane at much higher rates. These microsomes also exhibited high rates of p-nitrophenol oxidation. p-Nitrophenol is a model substrate mainly oxidized by P450 2E1 to p-nitrocatechol. Samples of human liver microsomes showed considerable differences in the extent of HCFC-123, p-nitrophenol oxidation, and chlorzoxazone hydroxylation. In human liver microsomes, rabbit anti-rat P450 2E1 IgG recognized a single protein band corresponding in apparent molecular weight to human P450 2E1. Immunoblot analysis revealed considerable heterogenity in the P450 2E1 protein content of the human liver samples. Trifluoroacetic acid formation from HCFC-123 and halothane and p-nitrocatechol formation from p-nitrophenol were significantly reduced by the P450 2E1 inhibitor diethyldithiocarbamate.(ABSTRACT TRUNCATED AT 250 WORDS)
Urban
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Institut für Toxikologie, Universität Würzburg, FRG.
Speerschneider
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Dekant
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D000818:Animals; D017402:Chlorofluorocarbons / Q000378:metabolism*; D064227:Chlorofluorocarbons, Ethane; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006221:Halothane / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D006221:Halothane