Metabolism in vivo and in vitro of the refrigerant substitute 1,1,1,2-tetrafluoro-2-chloroethane.
Ternary mixtures of hydrochlorofluorocarbons and hydrofluorocarbons are being evaluated as refrigerant substitutes for dichlorodifluoromethane, which is to be banned from further production in 2000. A priori consideration of the similarity between 1,1,1,2-tetrafluoro-2-chloroethane (HCFC-124), a primary component of candidate refrigerant blends, and halothane suggests that metabolism of HCFC-124 might proceed via reactive intermediates. Our data show that rats exposed for 2 hr to approximately 10,000 ppm HCFC-124 excreted both inorganic fluoride (F-) and trifluoroacetic acid (TFA), identified by 9F-NMR, in the urine. Likewise, microsomes produced F- and TFA from HCFC-124 in an NADPH-dependent, CO-inhibited, aerobic reaction. Treatment of rats with pyridine caused about a 20-fold increase in aerobic microsomal metabolism (F- release) of HCFC-124, while the rate of defluorination was slightly decreased by phenobarbital administration. An antibody to cytochrome P450 IIE1 inhibited more than 90% of HCFC-124 metabolism in pyridine-induced preparations. Defluorination of HCFC-124 by microsomes also occurred under conditions of greatly reduced oxygen tension, demonstrating that this halocarbon can be reductively metabolized. Moreover, heat-inactivated, NADPH-reduced microsomes liberated F- and a fluorinated organic product, although not TFA, from HCFC-124. Formation of TFA and F- as products of oxidative HCFC-124 metabolism support the hypothesis that trifluoroacetyl fluoride is formed as an intermediate. Trifluoroacetyl halides are known to adduct tissue proteins. The reductive metabolism of HCFC-124, by analogy to halothane, may produce a radical (CHFCF3) capable of biological interactions.(ABSTRACT TRUNCATED AT 250 WORDS)
Olson
M J
MJ
Biomedical Science Department, General Motors Research Laboratories, Warren, MI 48090-9055.
Johnson
J T
JT
O'Gara
J F
JF
Surbrook
S E
SE
D000818:Animals; D001711:Biotransformation / Q000502:physiology; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D005459:Fluorides / Q000032:analysis; D005461:Fluorine; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane; C072959:1,1,1,2-tetrafluoro-2-chloroethane; D005461:Fluorine; D003577:Cytochrome P-450 Enzyme System; D005459:Fluorides; D010100:Oxygen