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In vitro supporting data were available for Chloroacetamide, demonstrating a rapid drop in hepatocellular glutathione content, followed by lipid peroxidation, morphological changes and possible lysis of the treated cells. However during in vivo studies in rats, GSH depletion and morphological changes were demonstrated to be rapid and reversible within 24-48 hours, therefore Chloroacetamide led to rapid GSH depletion with possible  lipid peroxidation however without permanent damage of hepatocytes. 

Additional information

Supporting studies were available on the effect of Chloroacetamide on hepatic gluthatione (GSH). GSH is a co-factor for the selenium dependent GSH-peroxidase, and is important in the defence against lipid peroxidation. It has also become evident that GSH protects against protein alkylation and that compounds that deplete GSH may alkylate proteins, leading to cellular damage.

In an in vitro study, primary rat hepatocytes obtained from Sprague-Dawley rats were incubated for 4 to 5 hours with serum to which 18.7 µg chloroacetamide/mL had been added. There was a very sharp drop in cellular glutathione content in the first hour of incubation with Chloroacetamide, as well as a considerable enhancement of lipid peroxidation and marked lysis of the treated cells (Anundi et al., 1979). By adding methionine, which stimulates hepatocellular glutathione synthesis, it was possible to achieve clear inhibition of all of the effects described.

In an in vivo study, male Sprague-Dawley rats injected intraperioneally with 75 mg/kg bw Chloroacetamide, showed lesions in the liver parenchyma and enhancement of lipid peroxidation at 3 -6 h p.a., however morphological changes, notably hydropic degenerations, were reversible at 24 -48 h p.a. (Anundi et al., 1980). GSH content decreased rapidly; however at 1 h p.a. GSH increased and was slightly higher than normal at 48 and 72 h p.a.. Three to six hours after chloroacetamide administration, lesions developed in the peripheral midzonal parts of the hepatic lobules (swelling and hydropic degeneration). Hydropic degeneration of the hepatic lobules showed remission by 1/3 one week after treatment. A single intraperitoneal dose of 37.5 mg chloroacetamide/kg bw every second day also resulted in hepatocellular swelling and hydropic degeneration within 2 weeks. These changes were comparable with those seen after a single dose of 75 mg/kg bw.

Another study in male Sprague-Dawley rats investigated the effect of chloroacetamide on lipid peroxidation in vivo by means of the ethane/pentane breath test (Cluet & Boudène, 1983). Chloroacetamide was administered intraperitoneally at dose levels of 70, 80 and 150 mg/kg body weight. Upon treatment, the animals were immediately placed in closed breathing chambers with circulating air, and the amounts of ethane and pentane exhaled over periods of 2 and 4 hours were measured. Increases in the exhaled amounts of ethane and pentane were only small at 4 hours after the 70 mg/kg body weight dose, marked at 4 hours after the 80 mg/kg body weight dose and very marked at only 2 hours after the 150 mg/kg body weight dose. At the highest dose level, the animals died after 2 hours. The authors therefore saw the findings of Anundi et al. (1980) regarding chloroacetamide- induced stimulation of lipid peroxidation in vivo confirmed by an independent method.