VIII. PHARMACOLOGY 503 



a-Tocopherol. like ascorbic acid, is one of the few antioxidants capable 

 of passing the intestinal barrier, reaching intracellular sites, and exerting 

 regulatory control over cell oxidations. Despite hopes and a certain amount 

 of ('\i(lenco that tocopherol might prove to function in some oxidation-re- 

 duction system, or participate in some specific manner in certain enzyme 

 systems, no ck^ar-cut claims can yet be made; nor has there been produced 

 indisputable evidence that a-tocopheiol exerts biological effects unrelated 

 to its well-recognized function as an intracellular antioxidant. 



A. HYPERVITAMINOSIS E 



Xo state or syndrome of hypervitaminosis E has been described, nor is 

 there e\-idence that tocopherols per se e.xert any deleterious effect in ani- 

 mals or man. Dcmole^ has shown that mice will tolerate oi'al doses of 50 

 g. per kilogram, and rats doses of 4 g. per kilogram daily for 2 months. 

 Adult humans have tolerated oral doses of 1 g. per day for months, or larger 

 doses for shorter periods, with no undesii'able effects. Clinical literature 

 contains references to complaints of gastric distress and other symptoms 

 in patients on much smaller dosage levels; these are probabl}^ related to 

 fatty substances present in tocopherol concentrates or, in some instances, 

 to psychic factors. 



B. MODE OF ADMINISTRATION 



The natural and synthetic forms of a-tocopherol and their acetate esters 

 are viscous oils. Intramuscular injections, freciuently u.sed in clinical prac- 

 tice, have sometimes led to painful reactions locally and to oleogranulomas 

 at a later date;^ "solubilized" preparations may be less reactive in these 

 respects. Tocopherol ointments have been used to only a limited extent. 

 In animals, implanted pellets of the crystalline esters (palmitate, succinate, 

 and phosphate) produce marked local tissue reactions;'* so also does injec- 

 tion of the slightly water-soluble phosphate ester. Neither in animals nor 

 in man are there reliable data concerning the relative effectiveness of ab- 

 sorption and utilization of tocopherols administered in these various ways, 

 as compared to oral dosage which appears to he the most effective mode 

 of administration. 



C. METABOLIC STRESS IN ANIMALS 



There is a considerable body of evidence that a-tocopherol has a re- 

 markable capacity to protect experimental animals against a variety of 

 metabolic stresses, including those induced by anoxia, high intake of un- 

 saturated fats, low protein intake, restricted intake of oihor vitamins (.\, 



2 V. Demole, Inlern. Z. Vitaininfursch. 8, 33,S (193!)). 



3 C. L. Steinberg, Ann. AT. Y. Acad. Sci. 52, 380 (1949). 



* C. E. Tobin, Proc. Soc. Expil. Biol. Med. 73, 475 (1950). 



