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Vitamin E and hepatotoxic agents

3.* Vitamin E, synthetic antioxidants and carbon tetrachloride toxicity in the rat

Published online by Cambridge University Press:  09 March 2007

M. A. Cawthorne ,
J. Bunyan ,
M. V Sennitt ,
J Green  and
P. Grasso
M. A. Cawthorne
Affiliation:
Beecham Research Laboratories, Vitamins Research Station, Walton Oaks, Tadworth, Surrey
J. Bunyan
Affiliation:
Beecham Research Laboratories, Vitamins Research Station, Walton Oaks, Tadworth, Surrey
M. V Sennitt
Affiliation:
Beecham Research Laboratories, Vitamins Research Station, Walton Oaks, Tadworth, Surrey
J Green
Affiliation:
Beecham Research Laboratories, Vitamins Research Station, Walton Oaks, Tadworth, Surrey
P. Grasso
Affiliation:
British Industrial Biological Research Association, Carshalton, Surrey
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Abstract

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1. The acute toxicity of orally administered CCl4 and its subacute toxicity (liver necrosis and hepatic fat accumulation) were studied in young adult male and female rats. CCl4 was 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 CCl4 increased 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 CCl4 had 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 CCl4 not 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 CCl4 increased survival in male and female rats. When single doses of DPPD were given 6–48 h before CCl4 they 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 CCl4 were 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 CCl4 produced the same effect, but these single doses 24 or 6 h before CCl4 were 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 CCl4 was, 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.

Type
Research Article
Information
British Journal of Nutrition , Volume 24 , Issue 2 , June 1970 , pp. 357 - 384
Copyright
Copyright © The Nutrition Society 1970

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