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.