The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice


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Abstract

1,2-Dichloro-1,1,2-trifluoroethane (HCFC-123a) is a potential alternative to replace ozone-depleting chlorofluorocarbons. The metabolism of HCFC-123a was studied in microsomes of rats, mice, and humans as well as in rats and mice in vivo. Rat, mouse, and human liver microsomes metabolized HCFC-123a to inorganic fluoride and chlorodifluoroacetic acid. Fluoride formation was dependent on time and NADPH, HCFC-123a, and protein concentration. Microsomes from untreated rats oxidized HCFC-123a at low rates (0.49 nmol fluoride/20 min x mg protein). Pretreatment of rats with pyridine and ethanol, inducers of P450 2E1, increased the rates of fluoride release. In mouse liver microsomes, the rates of HCFC-123a oxidation to release fluoride were significantly higher (1.68 nmol fluoride/20 min x mg) than in rat liver microsomes. Incubation of HCFC-123a with microsomes and diethyldithiocarbamate (100 µM), an inhibitor of P450 2E1, reduced fluoride formation by more than 60%. In different samples of human liver microsomes, rates of fluoride formation were between two- and fourfold higher than those observed in liver microsomes from untreated rats. In rats and mice exposed to concentrations of HCFC-123a up to 5000 ppm in a closed recirculating exposure system, chlorodifluoroacetic acid, and inorganic fluoride were identified as urinary metabolites. The biotransformation of HCFC-123a in rats was saturated after exposure to more than 2000 ppm HCFC-123a for 6 h, whereas no saturation was evident in mice exposed to concentrations of up to 5000 ppm. The obtained results suggest a major role of P450 2E1 in the oxidation of HCFC-123a and in the different capacities for oxidative biotransformation of HCFC-123a in rodents. Mice may thus be more sensitive to toxic effects of HCFC-123a depending on biotransformation after administration of high doses.



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5370
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Dekant, W. , Assmann, M. and Urban, G. (1995): The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice , Toxicology and Applied Pharmacology, 135 , pp. 200-207 .


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