The role of CYP forms in the metabolism and metabolic activation of HCFCs and other halocarbons.
The use of hydrochlorofluorocarbons (HCFCs) such as HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-141b (1,1-dichloro-1-fluoroethane) is becoming widespread as replacements for the ozone depleting chlorofluorocarbons. Hepatic activation of HCFC-123 or the unsaturated perchloroethylene through oxidative pathways leads to the formation of the electrophiles trifluoroacetyl chloride or trichloroacetyl chloride, respectively. These can react with epsilon-NH(2) functions of lysine in proteins and give rise to neoantigens. In the case of HCFC-123, this reaction is catalysed primarily by CYP2E1 and to a much lesser extent by the constitutive CYP2C19, CYP2B6 and CYP2C8. For perchloroethylene, the extent of activation is less and the reaction is catalysed primarily by the CYP2B family. While acute hepatotoxicity has been seen in humans exposed to HCFC-123 or halothane, little short- or long-term toxicity in rodents is observed. No immunological related toxicity of perchloroethylene has been reported in exposed humans. Long-term exposure of rats can lead to renal tubule carcinomas and in mice, hepatocellular carcinomas. These toxic reactions do not appear to be directly related to the formation of the putative trichloroacetyl chloride intermediate.
White
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MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. iw6@le.ac.uk
De Matteis
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D000818:Animals; D006528:Carcinoma, Hepatocellular; D002384:Catalysis; D017402:Chlorofluorocarbons / Q000009:adverse effects* / Q000378:metabolism; D064227:Chlorofluorocarbons, Ethane; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced*; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D003577:Cytochrome P-450 Enzyme System; C068320:1,1-dichloro-1-fluoroethane