A. D. WELCH AND E. BUEDING 



and its structural analogue for some cellular component for which they 

 \ 1 / both have great affinity; in some cases, however, antagonism involves 

 other factors than simple competitive inhibition. In verification of 

 this concept, there have been developed various structural analogues 

 markedly antagonistic to the biological utilization of niacin, pyridoxine, 

 various amino acids, pantothenic acid, thiamin, riboflavin, ascorbic 

 acid, certain purines, biotin, and vitamin K. Against organisms 

 capable of synthesizing a given essential metabolite, the respective 

 analogues have in general been quite ineffective, the most notable of 

 the exceptions being of course, the sulfonamide group of drugs 

 (analogues of j&-aminobenzoic acid). 



The effect of metabolite-analogues is probably exerted through 

 their affinity for enzymes or for the protein components of enzymes, 

 the substrates, or the prosthetic groups which they resemble struc- 

 turally. The competitive type of antagonism of the metabolite- 

 analogues is usually comparable to that exhibited by substrates and 

 their analogues competing for isolated enzyme systems, for instance, 

 succinate and malonate in the presence of succinic dehydrogenase. 

 In such cases, the normal and the abnormal compounds antagonize 

 one another competitively and the kinetics of the reaction usually can 

 be explained with mathematical precision. Although none of the 

 analogues of the various essential metabolites so far prepared, with the 

 exception of the sulfonamides, has proved to be a practical chemo- 

 therapeutic agent, there is reason to believe that this approach will 

 prove to be fruitful. It would be remarkable indeed if the groping 

 which led to the discovery of the sulfonamides should have yielded the 

 only group of compounds of practical utility in the antagonism of an 

 essential metabolite. 



Another biochemical aspect of pharmacology to which more 

 attention should be given is concerned with the metabolic modification 

 of toxic or potentially toxic compounds. This process is generally 

 called "detoxication," a term which is misleading because it implies 

 that these compounds when metabolized are always converted into less 

 toxic substances. While this is generally true for compounds produced 

 in the body (for example, hormones), it is not always the case with 

 foreign substances (drugs, poisons, products of bacterial metabolism 

 in the intestine, such as indole and skatole). In some instances, 

 compounds of equal or even greater toxicity may be formed. It is 



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