EFFECTS OF THE TOCOPHEROLS AND THEIR PHOSPHATES ON ENZYME SYSTEMS

Vitamin E, or more specifically a-, @-, y-, and &tocopherols, functions in the body in some manner which is still unknown. The current working hypothesis is that vitamin E acts primarily and specifically through some enzyme system and, secondarily, in a non-specific manner as a physiological antioxidant. The general methods for approaching this problem fall logically into three main divisions: first, are the studies of the changes in enzyme systems which result from vitamin E deficiency; second, and very closely allied, are studies of changes in enzyme systems in which the tocopherols have been added irz vioo and i i t vitro; and, third, are studies dealing with the quite separate consideration of the action of the tocopheryl esters in wivo and on isolated enzyme systems. Severe vitamin E deficiency leads to a form of muscular dystrophy in many animals, characterized pathologically by the gradual replacement of normal muscle cells with fibrous tissue. Dystrophic tissues have an increased oxygen consumption' which may result in a high rate of respiration for the whole animal. A deficiency of vitamin E is unique in that it results in a stimulation of respiratory mechanisms. In addition, the dystrophy syndrome is accompanied by alterations in chemical composition and in functional behavior, of which the most striking are decreased muscIe creatine2 and marked creatinuria. The succinic dehydrogenase system is apparently ~naffected,~ but changes have been noted in the response of the lactic dehydrogenase system to digitoxin.4 General disturbances in phosphorylation mechanisms have been noted in dystrophic muscle, including the depression of coupled phosphorylations of creatine and the diminution of adenosine triphosphatase: The decrease in cholinesterase content of the tissues in vitamin E deficiency6 implies a close association of vitamin I3 and acetyl choline synthesis. The administration of a-tocopherol results in an immediate decrease in or even complete remission of the various changes associated with muscular dystrophy. When administered to normal animals, it has been reported to modify the metabolism of lipids and phospholipid^,^ to enhance phosphorylations,8 and to improve the metabolism of carbohydrate^.^ The addition of a-tocopherol, even when solubilized, to in vilro systems has no effect in most cases. However, a-tocopherol in minute concentrations has been shown to stimulate acetylcholine synthesis.I0 Furthermore, it inhibits lipoxidase, probably due to its action as an antioxidant.1' The study of the action of the tocopheryl esters on a number of isolated enzyme systems is currently of great interest. a-Tocopheryl phosphate (a-TPh), because of its water solubility, has played a commanding r61e. Orally administered, a-TPh can be readily hydrolyzed in the body,** and