Decrease in blood coagulation factors II (prothrombin), VII, IX and X in the rat after a single oral dose of butylated hydroxytoluene.

Abstract

Male Sprague-Dawley rats were given butylated hydroxytoluene (BHT) in a dose of 800 mg/kg body weight orally, and 0.5-72 hr later plasma concentrations of factors II, VII, IX and X and hepatic levels of BHT and BHT quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) were determined. Levels of factors II, VII, X and IX were reduced 36-60 hr after BHT treatment, but by 72 hr, those most affected (VII and IX) showed some recovery and X had returned to normal. Hepatic levels of BHT reached a maximum 3 hr (a major peak) and 24 hr after BHT dosing and BHT quinone methide reached a maximum at 6 and 24 hr (a major peak). In rats given BHT orally in doses of 200, 400 and 800 mg/kg, factors II, VII and X decreased after 48 hr only in rats given the highest dosage, but factor IX was more susceptible to BHT and showed a dose-dependent decrease. Phylloquinone (1 mg/rat) injected ip 24 hr after the administration of 800 mg BHT/kg maintained normal levels of factors VII and X and an almost normal level of factor IX, but had little effect on the level of factor II. In studies of the effects of drug-metabolizing-enzyme modifiers, neither ip pretreatment with 75 mg phenobarbital sodium/kg for 3 days nor the feeding of 1% cysteine in the diet throughout the experiment prevented the decrease in vitamin-K-dependent factors by 800 mg BHT/kg, but 2-day ip pretreatment with 60 mg cobaltous chloride/kg/day maintained normal levels of factors II and VII and reduced the BHT effect on factors IX and X. SKF 525A (50 mg/kg) injected ip either 30 min before or 12 hr after BHT treatment partially prevented the decrease in factors II, VII and X, or in all four factors, respectively. Thus the decrease in vitamin K-dependent factors may be the same with a single oral dose of BHT as with dietary BHT, and the anticoagulant effect may require the metabolic activation of BHT.