Vitamin E and hepatotoxic agents
Authors: Cawthorne M. A. , Bunyan J. , Sennitt M. V , Green J , Grasso P. 
Published: May 2005

1. The acute toxicity of orally administered CCl4and its subacute toxicity (liver necrosis and hepatic fat accumulation) were studied in young adult male and female rats. CCl4was more toxic in males than in females. The protective effects of vitamin E (D-α-tocopheryl acetate) and three synthetic antioxidants, DPPD (N,N'-diphenyl-p-phenylenediamine), ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) and BHT (butylated hydroxytoluene) were studied.

2. Three daily oral doses (450 mg/kg) of vitamin E given before CCl4increased survival in male rats but not consistently in females. Single oral doses (450 mg/kg) given previously at times between 24 and 72 h were also protective in males, but slightly decreased survival in females. Single intraperitoneal doses (500 mg/kg) given to female rats 1–48 h before CCl4had no effect on survival. None of these treatments with vitamin E significantly decreased CC14-induced hepatic triglyceride accumulation. A large oral dose (2000 mg/kg) 6 h before CCl4not only significantly increased hepatic fat accumulation but also increased mortality.

3. Three daily doses (600 mg/kg) of DPPD or a single oral dose given 72 h before CCl4increased survival in male and female rats. When single doses of DPPD were given 6–48 h before CCl4they had no effect on survival. In contrast, DPPD usually significantly decreased the CC14-induced hepatic triglyceride rise when given orally 6–72 h before CCl4. Single intra-peritoneal doses (100–1500 mg/kg) of DPPD, given 1–48 h before CCl4, decreased the hepatic triglyceride rise. Multiple doses of DPPD decreased CC14-induced liver necrosis, but single doses were generally less effective.

4. Three daily oral doses (300–500 mg/kg) of ethoxyquin given before CCl4were highly effective in preventing mortality, liver necrosis and the rise in hepatic triglycerides. Single oral doses (500 mg/kg) given 72 or 48 h before CCl4produced the same effect, but these single doses 24 or 6 h before CCl4were without effect. The effective treatments usually increased liver weight markedly. Intraperitoneal treatment with ethoxyquin also substantially reduced the toxicity of CC14. Ethoxyquin was the most effective of all four treatments studied, and livers from animals given this substance were often nearly normal in histological appearance.

5. The activity of oral doses (400–600 mg/kg) of BHT, given 48 h or more before CCl4was, in general, similar to that of ethoxyquin, but less marked. This substance also caused a large increase in liver weight after 48 h. Oral doses given 6–24 h before CC14 increased the CC14-induced triglyceride rise still further. Intraperitoneal doses of BHT were ineffective against acute toxicity, liver necrosis or the triglyceride rise.

6. Concentrations of a-tocopherol and the three synthetic antioxidants were measured in liver in many of the experiments. Very high hepatic concentrations of a-tocopherol could be obtained without affecting either the acute or subacute toxicity of CCl4. Ethoxyquin and BHT were rapidly eliminated from the liver after oral dosage, and when maximum concentrations were reached (24 h or less after administration) they were without protective effect. In contrast, when ethoxyquin and BHT were most active (48–96 h after administration) they could not be found in appreciable concentration in the liver.