Haemorrhagic toxicity of a large dose of α-, β-, γ- and δ-tocopherols, ubiquinone, β-carotene, retinol Acetate and l-ascorbic acid in the rat

Antioxidants occasionally have become prooxidants when a large amount was ingested. The haemorrhagic toxicity of butylated hydroxytoluene, a synthetic antioxidant, may involve such a mechanism. This study investigated whether haemorrhage is induced by overdoses of tocopherols, β-carotene, ubiquinone or l-ascorbic acid, which are representative biological antioxidants. Male Jcl:SD rats (six rats/group) were fed d-α-, d-β-, d-γ- or d-δ-tocopherols, ubiquinone Q-10, β-carotene or retinol acetate at a level of 0.5%, or l-ascorbic acid at 5% in the diet for 7 days. Only two rats given retinol acetate died with lung haemorrhages. Haemorrhages were observed in five or six, six, one, one, one or one of six surviving rats given d-α-, d-β- or d-γ-tocopherols, ubiquinone Q-10, β-carotene or retinol acetate, respectively (except for a retinol group in which four rats survived). Major haemorrhages were noted in the epididymis. In the α-, β- and γ-tocopherol, ubiquinone Q-10, β-carotene or retinol acetate-treated groups, prothrombin and kaoline-activated partial thromboplastin time indices were 26–28, 37, 59, 42, 63 and 65% or 27–28, 35, 65, 38, 59 and 28%, respectively, of the control values. Only the prothrombin index was significantly decreased to 67% in δ-tocopherol-administered rats, whereas controls and those receiving l-ascorbic acid showed no signs of bleeding or coagulation defect. The same tendency was also seen in the decreasing effect on vitamin K-dependent blood coagulation factors. These results suggest that the four naturally occurring tocopherols have a tendency to cause haemorrhage in the order of α > β > γ > δ, and ubiquinone Q-10 and β-carotene also have relatively strong and weak haemorrhagic effects, respectively, with regard to prothrombin and partial thromboplastin time indices.