The chlorofluorocarbon substitute
1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) is a structural analog of
halothane. Both are oxidatively metabolized by CYP2EI, producing a reactive trifluoroacyl
acid chloride intermediate and have been shown to cause acute liver
necrosis in the guinea pig. With
halothane, liver injury has been associated with the degree of reactive intermediate binding to hepatic
protein. This injury can be potentiated by prior
glutathione (GSH) depletion. Thus, the combination of GSH depletion and
HCFC-123 exposure was evaluated for its hepatotoxic potential in this species. Male outbred Hartley guinea pigs were injected with either 0.8 g/kg l-
buthionine-(S,R)-sulfoximine (BSO) to deplete hepatic
glutathione or vehicle control
solution 24 hr before a 4-hr inhalation exposure to 1.0% (v/v)
HCFC-123 with 40% O2.
HCFC-123 caused minimal liver injury with only 1 of 8 exposed animals displaying confluent zone 3
necrosis. GSH depletion potentiated injury producing submassive to massive liver
necrosis in some animals. This potentiation was associated with a 36% increase in covalent binding of reactive
HCFC-123 intermediates to hepatic
protein. These results were not due to alterations in the biotransformation of
HCFC-123 as indicated by plasma concentrations of the metabolites
trifluoroacetic acid and
fluoride ion which were not affected by BSO pretreatment.
HCFC-123 was also found to cause a decrease in liver GSH concentrations following exposure. These findings demonstrate a role for hepatic GSH in helping to prevent covalent binding by the trifluoroacyl
acid chloride intermediate. Inhalation of
HCFC-123 can cause acute hepatic injury in the guinea pig that is worsened by low hepatic GSH concentrations.