The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice.
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 microM), 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 hr, 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.
Dekant
W
W
Institut für Toxikologie, Universität Würzburg, Federal Republic of Germany.
Assmann
M
M
Urban
G
G
D000818:Animals; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000378:metabolism*; D064227:Chlorofluorocarbons, Ethane; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005459:Fluorides / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D004791:Enzyme Inhibitors; D011725:Pyridines; C097537:1,2-dichloro-1,1,2-trifluoroethane; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C023666:pyridine; D005459:Fluorides