6 1. PERSPECTIVES OF METABOLIC INHIBITION 



activity can be arranged and controlled in a multiplicity of ways. Indeed, 

 the specificity of the effects observed on certain tissues when the inhibitors 

 are administered to whole animals is presumptive evidence for the meta- 

 bolic differentiation of tissues. 



The physiologist, whether interested in plants or animals, turns to en- 

 zyme inhibitors to establish relationships between the functional aspects 

 of cellular activity and the metabolic systems supplying the energy and the 

 materials necessary for these functions. Perhaps the most commonly used 

 substances have been the uncouplers of oxidative phosphorylation in order 

 to demonstrate the role of high-energy phosphate compounds in cellular 

 processes. There are many other well-known studies in which inhibitors 

 have aided our understanding of the metabolic basis of function: the in- 

 vestigations of nerve and muscle membrane potentials by Hodgkin, Shanes, 

 and Gerard; the elucidation of various active transport or secretory mech- 

 anisms, in the kidney by Taggart and Mudge, in the gastric mucosa by 

 Davenport, in the intestine by Visscher and Quastel, in the erythrocytes 

 by Parpart, LeFevre, and Wilbrandt, and in plants by Lundegardh; the 

 investigation of muscle contraction by Lundsgaard; the studies of cell di- 

 vision by Runnstrom, Clowes, and Krahl; and the determination of the role 

 of acetylcholine in many tissues by Loewi and others. Despite the large 

 amount of work done, only a modest degree of success has been achieved 

 in accurately relating function to metabolism, due mainly to the complexity 

 of the situation, but it is likely that this use of inhibitors will become in- 

 creasingly important as the blocking can be made more selective. 



The relationship between enzyme inhibition and pharmacology is so close 

 that it would be very difficult (and useless) to draw a line between them. 

 Some would prefer a broad definition wherein all substances acting on living 

 matter are called drugs, so that inhibitors would then be considered as 

 drugs and come under the field of pharmacology. Systems of classification 

 here are not very important and we shall generally restrict the use of the 

 term drug to substances currently useful in medicine. Substances such as 

 carbon monoxide, which are important toxicologically and are discussed 

 in the standard pharmacology texts, and yet are also classic enzyme inhi- 

 bitors, will be considered for practical purposes as inhibitors. In some cases 

 the decision must be arbitrary. Some organic mercurials are widely used 

 as diuretics in edematous states and their actions are probably attributable 

 to an interference with renal metabolism in a manner similar to the actions 

 of those mercurials, such as p-chloromercuribenzoate, used by biochemists 

 to detect sulfhydryl groups on enzymes. Inhibitors of carbonic anhydrase 

 (acetazoleamide, chlorothiazide, and the recent derivatives), cholinesterase 

 (physostigmine, neostigmine, and the organophosphorus compounds), and 

 monoamine oxidase (iproniazid and derivatives) are very commonly used 

 in medicine, and it is likely that other enzyme inhibitor groups will be cli- 



