EFFECTS ON GLYCOLYSIS 485 



Tiedemann et al. (1958) reported that the inhibitions of ascites tumor cell 

 aerobic glycolysis by 0.04 milf menadione are 87% with glucose, 57% 

 with glucose-6-P, and 40% with fructose- 1,6-diP as substrates, these results 

 indicating significant inhibitions of hexokinase and some enzyme distal to 

 fructose- 1,6-diP (probably 3-phosphoglyceraldehyde dehydrogenase), with 

 a minor action on phosphohexokinase. 9,10-Phenanthraquinone causes an 

 accumulation of glucose-6-P (2x ), fructose- 1,6-diP (10 X ), and 3-phospho- 

 glyceraldehyde (4-5 X ) in ascites cells (Tiedemann and Risse, 1960), which 

 might be taken as indicating inhibitions of phosphohexokinase and 3-phos- 

 phoglyceraldehyde dehydrogenase, but it was also shown that this quinone 

 rapidly reduces both ATP and NAD levels in glycolyzing cells so that a sub- 

 stantial part of the inhibition may be related to this rather than to a direct 

 action on the enzymes. Holzer (1956) and Holzer et al. (1956) favored 3- 

 phosphoglyceraldehyde dehydrogenase as the primary site of inhibition on 

 the basis of comparative studies with a variety of carcinostatic quinones, 

 and Cohen and Hochstein (1960) also prefer this site for the inhibition of 

 brain glycolysis. On the other hand, Kiesow (1960 a) found that menadione 

 rather potently reduces the uptake of 2-deoxyglucose by yeast, this being 

 presumably a measure of hexokinase inhibition, and since the effects are 

 about the same as on fermentation this enzyme was considered to be a major 

 site of attack. Summarizing all of this evidence, one can conclude only 

 that both hexokinase and 3-phosphoglyceraldehyde dehydrogenase are 

 usually inhibited and represent the important glycolytic inhibition sites, 

 with phosphohexokinase contributing to a minor extent, and that all of 

 the inhibition may be not directly on these enzymes but also dependent 

 on reduction of ATP and NAD levels. In this connection it is important to 

 remember that hydrogen peroxide is a potent inhibitor of glycolysis and is 

 formed aerobically during the oxidation of hydroquinones. Hochstein and 

 Cohen (1960 a) pointed out that glycolysis in brain homogenates is very 

 sensitive to quinones and that protection is afforded by supernatant frac- 

 tions from other tissues, part of this protection being related to the catalase 

 content. Putter (1963) demonstrated that quinones increase the hydrogen 

 peroxide levels in ascites tumor cells, and postulated that the falls in 

 ATP and NAD could well be related to this. Inhibitions of anaerobic gly- 

 colysis would, of course, not be attributed to hydrogen peroxide. 



The understanding of how naphthoquinones alter glucose metabolism in 

 brain has recently been enlarged by the excellent studies of Hoskin using 

 K+-stimulated guinea pig cortex slices. Menadiol-diP, which presumably 

 is active by virtue of the menadione formed from it, was shown to alter 

 the pattern of glucose metabolism in a characteristic way (see accompanying 

 tabulation) (Hoskin, 1960 b). There is a slight stimulation of the respi- 

 ration and scarcely any effect on the C^^Og derived from glucose-6-C^*, 

 but the formation of C^^Og from glucose- l-C^* is markedly augmented so 



