Role of P4502E1 in the metabolism of 1,1,2,2-tetrafluoro-1-(2,2,2-trifluoroethoxy)-ethane.
1. The metabolism of 1,1,2,2-tetrafluoro-1-(2,2,2-trifluoroethoxy)-ethane (HFE), a prospective chlorofluorocarbon alternative, was studied in rat and human liver microsomes and in rat in vivo. 2. HFE was metabolized to inorganic fluoride, trifluoroacetaldehyde hydrate, trifluoroacetic acid and difluoroacetic acid, which were identified by 19F-nmr in microsomal incubation. After i.p. dosing with 200 mg/kg HFE to rat, trifluoroacetic acid and trifluoroacetaldehyde hydrate were identified as urinary metabolites. 3. The formation of inorganic fluoride from HFE was used to quantify oxidative metabolism. In liver microsomes from untreated rat, formation of inorganic fluoride could not be detected. However, microsomes from rats treated with P4502E1 (2E1) inducers ethanol and pyridine catalysed the formation of fluoride at different rates. The extent of fluoride formation in microsomes correlated with the amount of 2E1 protein as determined by immunoblots with a polyclonal antibody and with the extent of oxidation of p-nitrophenol and chlorzoxazone, two specific substrates for 2E1. 4. In different samples of human liver microsomes, the formation of inorganic fluoride correlated well with the ability of the microsomes to oxidize chlorzoxazone and p-nitrophenol and the amount of 2E1 protein as determined by immunoblots. 5. The obtained results suggest that 2E1 plays a major role in the metabolism of HFE in rat and man.
Institut für Toxikologie, Universität Würzburg, Germany.
J
J
Herbst
U
U
Köster
R
R
Kerssebaum
W
W
Dekant
D000818:Animals; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004980:Ethane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005459:Fluorides / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics*; D015151:Immunoblotting; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005466:Fluorocarbons
D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System; D004980:Ethane; D005459:Fluorides; D006845:Hydrocarbons, Fluorinated; D010089:Oxidoreductases, N-Demethylating; C090336:1,1,2,2-tetrafluoro-1-(2,2,2-trifluoroethoxy)ethane; D005466:Fluorocarbons