D. W. WOOLLEY 



Studies carried out with it. The compound was not discovered be- 

 cause of its structural similarity to vitamin K— only after its pharma- 

 cological properties were recognized was its structural similarity 

 to vitamin K seen, and its reversal by the vitamin demonstrated. 

 With this glance backward to fortify us, let us look further in this 

 direction. 



The study of a-tocopherol quinone represents the next step along 

 the path. Tocopherol deficiency, at least in the first generation of 

 rats or mice, manifests itself in females, to a large degree, by resorption 

 of embryos during gestation. Other signs are generally not seen. 

 Therefore, it was thought that the development of a successful antago- 

 nistic analogue of tocopherol would serve as an example of what might 

 be done along lines of application to pharmacology of studies in bio- 

 chemical antagonisms. In due course it was demonstrated that a- 

 tocopherol quinone in sufficient doses caused hemorrhage and resorp- 

 tion of the embryos of pregnant mice. 



Despite the fact that results siinilar to those of tocopherol deficiency 

 were achieved by administration of tocopherol quinone, tocopherol even in 

 large doses did not reverse these signs. It was of considerable interest to find 

 that vitamin K in very small quantities would prevent the vaginal hemor- 

 rhages which immediately preceded resorption. When these hemorrhages 

 were eliminated by vitamin K, the pharmacological effectiveness of the 

 quinone was markedly reduced. It was then realized that tocopherol quinone 

 is a structural analogue of vitamin K as well as of tocopherol. The action of 

 the quinone, however, differed from that of such an antivitamin K as 3,3'- 

 methylenebis-[4-hydroxycoumarin] in its selective action on pregnant animals 

 and in the fact that the coumarin did not produce similar signs. 



When similar quantities of a-tocopherol quinone were given to 

 nonpregnant mice, no detectable signs of disease were observed. Al- 

 though these steps have been made along the path under considera- 

 tion, the final one has not been taken — the production of a thera- 

 peutically useful agent. 



One of the features of the action of tocopherol quinone should be 

 discussed since it illustrates a general principle in the use of inhibitory 

 analogues related structurally to metabolites. Almost without excep- 

 tion the effective dose of an antagonist is very large compared with the 

 amount of metabolite involved. In other words, the ratio of inhibitor 



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