Pentahaloethane-based chlorofluorocarbon substitutes and halothane: correlation of in vivo hepatic protein trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation.
The hydrochlorofluorocarbons (HCFCs) 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) and 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124) and the hydrofluorocarbon (HFC) pentafluoroethane (HFC-125) are being developed as substitutes for chlorofluorocarbons that deplete stratospheric ozone. The structural similarity of these HCFCs and HFCs to halothane, which is hepatotoxic under certain circumstances, indicates that the metabolism and cellular interactions of HCFCs and HFCs must be explored. In a previous study [Harris et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 1407], similar patterns of trifluoroacetylated proteins (TFA-proteins) were detected by immunoblotting with anti-TFA-protein antibodies in livers of rats exposed to halothane or HCFC-123. The present study extends these results and demonstrates that in vivo TFA-protein formation resulting from a 6-h exposure to a 1% atmosphere of these compounds follows the trend: halothane approximately HCFC-123 much greater than HFC-124, greater than HFC-125. The calculated enthalpies of activation of halothane, HCFC-123, HCFC-124, and HFC-125 paralleled the observed rate of trifluoroacetic acid excretion in HCFC- or HFC-exposed rats. Exposure of rats to a range of HCFC-123 concentrations indicated that TFA-protein formation was saturated at an exposure concentration between 0.01% and 0.1% HCFC-123. Deuteration of HCFC-123 decreased TFA-protein formation in vivo. Urinary trifluoroacetic acid excretion by treated rats correlated with the levels of TFA-proteins found after each of these treatments. No TFA-proteins were detected in hepatic fractions from rats given 1,1,1,2-tetrafluoroethane (HFC-134a), which is not metabolized to a trifluoroacetyl halide.(ABSTRACT TRUNCATED AT 250 WORDS)
Harris
J W
JW
Department of Pharmacology, University of Rochester School of Medicine, New York 14642.
Jones
J P
JP
Martin
J L
JL
LaRosa
A C
AC
Olson
M J
MJ
Pohl
L R
LR
Anders
M W
MW
D000818:Animals; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D004591:Electrophoresis, Polyacrylamide Gel; D005466:Fluorocarbons / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015151:Immunoblotting; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014269:Trifluoroacetic Acid / Q000652:urine*
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane; D005466:Fluorocarbons; D011506:Proteins; C072959:1,1,1,2-tetrafluoro-2-chloroethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; C078256:pentafluoroethane; D014269:Trifluoroacetic Acid