PART IV 

 INTERMEDIATE METABOLISM 



FREE RADICALS DERIVED FROM TOCOPHEROL AND 

 RELATED SUBSTANCES 



L. MICHAELIS and S. H. WOLLMAN * 



Laboratories of the Rockefeller Institute for Medical Research, 

 Neiv York.N.Y. {U.S.A.) 



Tocopherol is known to exhibit two properties: It serves as a vitamin, and also as 

 an antioxidant with respect to the autoxidation of unsaturated fatty acids. The latter 

 property is shared with many substances of phenolic character. Although the mechanism 

 of the antioxidant effect is not fully understood, and the mechanism of its effect as 

 vitamin E is not understood at all, the suggestion as to some lelationship of those two 

 effects is almost inescapable. The vitamin effect may be closely related to the antioxidant 

 effect, except of course for the fact that the more specific effect of the vitamin requires 

 a special structure in addition to the general feature of being a substituted hydroquinone. 

 It may be left undecided whether the specific structure is just to make it more fat- 

 soluble or to adapt it to any function as a coenzyme to some enzyme. 



Hydroquinone is an efficient antioxidant^. Although the mechanism of its action 

 is not known in every respect, it can scarcely be doubted that this effect is in some way 

 connected with its reversible oxidizability. However, also phenols with only one (or 

 at least one unsubstituted) hydroxyl group are antioxidants^. Here no reversible 

 oxidation comparable with that of hydroquinone can take place. The reversible oxida- 

 tion of hydroquinone leads to quinone, by a bivalent oxidation passing through the 

 intermediate stage of a semiquinone. For monophenols, no such bivalent reversible 

 oxidation is imaginable. However, a reversible univalent oxidation to a free radical is 

 imaginable both for hydroquinone and for mono-phenols**, including tocopherol. Such 

 a radical would be a rather unstable compound. Ordinary oxidizing agents may not be 

 able to produce the semiquinone radicals to any readily recognizable extent; yet, if 

 a free radical may be produced only to a slight extent, not recognizable directly, the 

 high energy content of the radical would make it a powerful reactant; just as the fiee 

 OH radical, although never existing to any directly recognizable extent in an aqueous 

 solution, has been recognized as a powerful reagent in many chain reactions. 



However, any speculation about such free radicals is all too vague unless there is 

 more direct evidence for their existence. It is the purpose of this paper to produce such 

 evidence. It is based on a method devised by G. N. Lewis^' * and consists of the following 

 procedure. The substance to be oxidized is dissolved in an organic solvent such as, at 

 the temperature of liquid air, will freeze to a homogeneous glass without crystallizing, 



* Special Research Fellow of the National Cancer Institute. 

 ** At the present time, it will not be discussed whether even one unsubstituted hydroxyl grou]) 

 is necessary at all for the establishment of a free radical of comparable structure. 



References p. i^g. 156 



