1. PERSPECTIVES OF METABOLIC INHIBITION 7 



nically applied in the future. It is indeed possible that many of the drugs 

 whose actions are at present unknown are inhibitors of enzymes or in other 

 ways disrupt metabolism. The recent classification and mathematical ex- 

 position of drug antagonisms and synergisms by Ariens and his co-workers 

 are simply enzyme inhibition kinetics applied to drug actions and his equa- 

 tions have their counterparts in the classical inhibition formulations. En- 

 zyme inhibitors can, of course, be useful to the pharmacologist in the ana- 

 lysis of the site and manner of action of drugs, particularly when the drugs 

 affect directly or indirectly some metabolic processes. 



One of the most interesting facets of enzyme inhibition is the production 

 in animals of metabolic blockades which become manifest as syndromes 

 resembling certain diseased states. The pathologist is occasionally able 

 to learn something about disease processes from the study of such artificially 

 induced biochemical lesions resulting from the controlled use of enzyme 

 inhibitors. There are numerous examples: the inflammation, vesication, and 

 neuritis produced by the arsenicals, the induction of pseudocoeliac disease 

 in rats with iodoacetate, the diabetic state from alloxan, the occurrence of 

 obesity after the administration of the dithiocarbamates, the carcino- 

 genicity of many inhibitors, the deficiency states brought about by analogs 

 of essential coenzymes and by substances inactivating these coenzymes, and 

 the abnormal mental states sometimes following the monoamine oxidase 

 inhibitors. There is a wide field to be explored in the tracing of the progres- 

 sive pathological changes occurring during chronic administration of sub- 

 stances disturbing metabolism in various ways. This would be the study 

 of the sequence of cellular changes initiated by selective metabolic alteration 

 in contrast to the observation of the immediate effects. There is also the 

 possibility that naturally occurring inhibitors may be responsible for some 

 diseases and many of such inhibitors are now known. 



These relationships of enzyme inhibition to other disciplines point to 

 the fact that the study of inhibition is one of the common meeting grounds 

 of many diverse fields. This is also shown by the appearance of publications 

 on inhibitors in journals of every type — chemical, biological, medical, and 

 industrial. There is perhaps some need in in'esent-day science to establish 

 fields that cut across many others in order to combat the excessive compart- 

 mentalization that has inevitably developed. In the study of enzyme and 

 metabolic inhibition one soon loses any conception of the artificial bound- 

 aries of these many fields and comes to look upon the study of living matter 

 as the only subject to be pursued. 



Inasmuch as there is no general account of the history of the use of in- 

 hibitors, it may not be out of place here to present a short summary of 

 this development against the background of enzymological and biochemical 

 history. The first recognition of an enzyme was by Payen and Persoz in 1830 

 when they observed the splitting of starch by a substance they called dias- 



