Effect of 18 HR fast and glutathione depletion on 1,1-dichloroethylene-induced hepatotoxicity and lethality in rats

Abstract

Four-hour inhalation exposure to 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) was more injurious to 18-hr (overnight) fasted rats than to rats fed ad libitum. The estimated 24 hr LC50 for fed rats was 15,000 ppm while the same value for fasted rats was 600 ppm. The minimum lethal concentration was 200 ppm for fasted rats and 10,000 ppm for fed rats. Serum alanine α-ketoglutarate transaminase (AKT) elevation occurred at 150 ppm in fasted rats, but in the fed rats, a significant elevation was only seen at 2000 ppm and higher. Elevated serum AKT preceded hepatic necrosis and death. This fed-fasted difference in serum AKT elevation was also demonstrable in an isolated perfused rat liver system. The AKT elevation in perfusate from livers of fasted rats was consistent with the time course of injury seen in vivo. Increased susceptibility to hepatic injury appeared to be related to decreased hepatic glutathione concentration associated with fasting (18 hour). Diethylmaleate, a material which results in a decreased hepatic glutathione concentration was administered in vivo and in vitro. This treatment potentiated the hepatic injury in fed rats and in livers taken from fed rats and subsequently perfused.