Metabolism of 1,2-dichloro-1-fluoroethane and 1-fluoro-1,2,2-trichloroethane: electronic factors govern the regioselectivity of cytochrome P450-dependent oxidation.
1,2-Dichloro-1-fluoroethane (HCFC-141) and 1,1,2-trichloro-2-fluoroethane (HCFC-131) were chosen as models to study the regioselectivity of halogenated alkane metabolism. Metabolites in the urine of rats given HCFC-131 ip were the following: inorganic fluoride, chlorofluoroacetic acid, dichloroacetic acid, N-(2-hydroxyethyl)chlorofluoroacetamide, and three unidentified minor metabolites. In vitro incubation of HCFC-131 with either rat liver microsomes from pyridine-treated rats or expressed human cytochrome P450 2E1 isozyme in the presence of NADPH gave fluoride, chlorofluoroacetic acid, and dichloroacetic acid as metabolites. HCFC-141 was biotransformed in rats to inorganic fluoride, chlorofluoroacetic acid, 2-chloro-2-fluoroethanol, and 2-chloro-2-fluoroethyl glucuronide, which were detected in urine. Incubation of HCFC-141 with NADPH-fortified liver microsomes from pyridine-induced rats or expressed human cytochrome P450 2E1 afforded fluoride, chlorofluoroacetaldehyde hydrate, and chloroacetic acid as products. The metabolites identified were consistent with a cytochrome P450-dependent oxidation mechanism. The data also indicated that phosphatidylethanolamine may be a cellular target for chlorofluoroacetyl chloride, a reactive intermediate generated from HCFC-131 by cytochrome P450-dependent oxidation. Chlorofluoroacetic acid given to rats ip was largely recovered in the rat urine, although the formation of inorganic fluoride as a metabolite was observed. The mechanism of defluorination of chlorofluoroacetic acid is not clear. Regioselective oxidation by cytochrome P450 was observed between the two potential oxidizable sites in HCFC-141 and in HCFC-131. Comparison of the observed ratio of oxidation at different sites in in vitro experiments with the calculated activation energies for hydrogen-atom abstraction from these sites indicated that electronic factors are the primary determinant of regioselectivity. In vivo regioselectivity could not be compared with theory since this ratio does not reflect the true regioselectivity due to differences in excretion, reabsorption, secondary metabolism (e.g., fluoride generation from chlorofluoroacetic acid), other routes of fluoride formation, and limitation of the method of detection.
Yin
H
H
Department of Pharmacology, University of Rochester, New York 14642, USA.
Anders
M W
MW
Jones
J P
JP
D000818:Animals; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000493:pharmacokinetics* / Q000652:urine; D064227:Chlorofluorocarbons, Ethane; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013379:Substrate Specificity
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; C093873:1,1,2-trichloro-1-fluoroethane; D003577:Cytochrome P-450 Enzyme System; C068320:1,1-dichloro-1-fluoroethane