BIOCHEMICAL ANTAGONISM 



to metabolite is generally large.* Therefore, the required close of an 

 inhibitor depends on two things: tlie intrinsic activity of the metabo- 

 lite, and the ratio between metabolite and inhibitor which is neces- 

 sary for reversal. This latter ratio may vary widely among species 

 for the same inhibitor-metabolite pair. Now, tocopherol is a rela- 

 tively inactive vitamin as vitamins go. The effective dose in a rat 

 is about three milligrams as compared with a small per cent of this 

 amount for several other vitamins. Hence it was foreseen that very 

 large doses of tocopherol quinone would probably be required to 

 produce the effect; and this proved to be the case. 



Antagonistic analogues of hormones may eventually find 

 practical application. It is now believed that certain diseases result 

 from overproduction, or diminished rate of destruction, of various 

 hormones. A possible method of treating such diseases may be by 

 administering an inhibitory analogue of the substance concerned. 

 The analogue would, in effect, remove the excessive amounts of the 

 hormone. A few such inhibitory analogues have already been pro- 

 duced, but the hormones to which they are related have not yet been 

 implicated as causative agents of disease as a result of overproduction 

 in the organism. It has therefore not been possible to test this in- 

 triguing postulate. 



Because it had its beginnings in investigations of the action of 

 sulfonamides, work on inhibitory compounds related structurally to 

 metabolites has had a strong flavor of bacteriostasis. This has been 

 increased by the fact that a most fruitful method of determining whether 

 a given analogue behaves antagonistically with its related metabolite 

 has been to make observations on the effect on growth of microbial 

 species. Most of the early attention was directed toward the develop- 

 ment of chemotherapeutic agents which would be effective against 

 infectious diseases. Mcllwain and Hawking were able to show that 

 this method of approach held promise when they demonstrated that 

 thiopanic acid could prevent experimental infection of rats with 

 hemolytic streptococci. However, the amounts of the agent required 



* Thus far, only in the cases of benzimidazole and of 3,3'-methylenebis- 

 [4-hydroxycoumarin] has the ratio been 1 : 1 or less. In these two exceptions the 

 quantity of inhibitor required for an effect was large, but once an adequate level 

 of the agent was established the ratio between inhibitor and metabolite was small. 



