452 9. INHIBITION IN CELLS AND TISSUES 



fundamental cliange brought about by the inhibitor. Possible mechanisms 

 for such behavior will be discussed presently. Lastly, a substance may ex- 

 hibit a biphasic action involving stimulation at lower concentrations and 

 inhibition at higher concentrations. The primary action of interest may 

 be the inhibition, for which the substance is being used, but unfortunately 

 the substance exerts both actions despite the purpose of the investigation. 



Although many examples of various types of stimulation brought about 

 by enzyme inhibitors will be given in the chapters on the inhibitors, a few 

 illustrations of the phenomenon may serve to make the presentation more 

 concrete. Arsenite, although a general enzyme inhibitor, has been found to 

 stimulate papain (Bersin, 1934), malic dehydrogenase (Green, 1936), uric- 

 ase (Mahler et al., 1955), hexose diphosphatase (Peters et al., 1946), and 

 the Pj-ATP exchange enzyme (Plant, 1957). Likewise, it has been shown to 

 stimulate resi)iration of spermatozoa (Barron et al., 1948b; Humphrey, 

 1950), diatoms (Lewin, 1955), Trichomonas (Ryley, 1955), and yeast (Shac- 

 ter, 1953), despite the fact that in most cells or tissues a marked inhibition 

 is observed. Some of the quinones, although very inhibitory to enzymes 

 such as papain, ijroteinases, pyruvic decarboxylase, urease, and lipase, are 

 known to stimulate deoxyribonuclease (Hoffmann-Ostenhof and Frisch- 

 Niggemeyer, 1952); and, although inhibitory to the respiration of many 

 tissues, they may stimulate that of Arbacia eggs (Anfinsen, 1947), sperma- 

 tozoa (Lardy and Phillips, 1943), mammalian erythrocytes (Friedheim, 

 1934; Supniewski et al., 1936), and mouse liver and muscle (Supniewski 

 et al., 1936). Phenylmercuric compounds inhibit succinoxidase (Cleland, 

 1949) and muscle ATPase (Polls and Meyerhof, 1947) almost completely 

 at 1 mM but both enzymes are stimulated by concentrations around 

 0.01 mM. An interesting example of selective stimulation has been found 

 in yeast (Lundsgaard, 1930b; Nilsson et al., 1931), where iodoacetate at 

 a concentration almost completely inhibiting fermentation may have a 

 stimulating effect on respiration. The ability of malonate to increase the 

 utilization of substrates such as /5-ketoglutarate in heart mitochondria has 

 been reported (Slater and Holton, 1954) and we have noted a 15-30% 

 increase in pyruvate incorporation in such mitochondria when low con- 

 centrations of malonate are used. The biphasic action is i^articularly well 

 shown in the actions of fluoride and azide on the endogenous respiration 

 of yeast (Borei, 1942). In the case of fluoride, a stimulation greater than 

 100% may occur at 20 mM, while at 30 mM a 70% inhibition takes its 

 place. These are only a few randomly chosen examples of stimulation but 

 they are perhaps suffcient to indicate the widespread occurrence of this 

 effect and the different ways in which it may be manifested. 



There are many possible mechanisms which may be hypothesized to 

 explain these instances of stimulation but there is little experimental evi- 

 dence to implicate a particular mechanism in any situation. Some of the 



