Haemorrhagic toxicity of a large dose of alpha-, beta-, gamma- and delta-tocopherols, ubiquinone, beta-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, beta-carotene, ubiquinone or L-ascorbic acid, which are representative biological antioxidants. Male Jcl:SD rats (six rats/group) were fed d-alpha, d-beta, d-gamma or d-delta-tocopherols, ubiquinone Q-10, beta-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-alpha, d-beta or d-gamma-tocopherols, ubiquinone Q-10, beta-carotene or retinol acetate, respectively (except for a retinol group in which four rats survived). Major haemorrhages were noted in the epididymis. In the alpha-, beta- and gamma-tocopherol, ubiquinone Q-10, beta-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 delta-tocopherol-administered rates, 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 alpha > beta > gamma > delta, and ubiquinone Q-10 and beta-carotene als0o have relatively strong and weak haemorrhagic effects, respectively, with regard to prothrombin and partial thromboplastin time indices.
Takahashi
O
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Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
D000276:Adjuvants, Immunologic / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D001205:Ascorbic Acid / Q000633:toxicity*; D001777:Blood Coagulation / Q000187:drug effects; D002338:Carotenoids / Q000633:toxicity*; D004224:Diterpenes; D004822:Epididymis / Q000187:drug effects; D005094:Exophthalmos / Q000139:chemically induced; D005123:Eye / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced*; D008297:Male; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D000084562:Retinyl Esters; D013237:Stereoisomerism; D013925:Thromboplastin / Q000187:drug effects; D014451:Ubiquinone / Q000633:toxicity*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000633:toxicity; D014810:Vitamin E / Q000633:toxicity*; D019207:beta Carotene
D000276:Adjuvants, Immunologic; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004224:Diterpenes; D000084562:Retinyl Esters; D019207:beta Carotene; D014801:Vitamin A; D014451:Ubiquinone; D014810:Vitamin E; D002338:Carotenoids; C009166:retinol acetate; D013925:Thromboplastin; D001205:Ascorbic Acid