184 1. MALONATE 



onate. This has been shown particularly clearly in brain slices, stimulated 

 both electrically (Heald, 1953) and by K+ (Kimura and Niwa, 1953; Yoshida 

 and Quastel, 1962). The stimulated respiration is readily inhibited by mal- 

 onate (Fig. 1-14) whereas the resting respiration is insensitive. This be- 

 havior is probably exhibited by many tissues. It is often very difficult to 

 determine exactly the functional state of isolated tissues, such as slices, 

 but where possible this should be attempted. We shall find later that 

 active tissues are more easily functionally depressed by malonate and 

 this may have a metabolic basis. Indoleacetate stimulates the growth of 

 Avena coleoptiles and increases the respiration simultaneously. This ad- 

 ditional respiration brought about by indoleacetate is readily inhibited by 

 malonate (Bonner, 1949), and it is likely that the respiration of rapidly 

 growing tissue is generally inhibited more strongly by malonate than that 

 of resting or slowly proliferating tissue. 



Consideration must also be given to the history of the tissue. Bonner (1948) 

 has shown that the nutritional state of the Avena coleoptile determines the 

 inhibition by malonate, and it is probable that the same applies to animal 

 tissues. The inhibition of wheat seedling respiration by malonate depends 

 on a number of factors, including the type and duration of irradiation, 

 the nutrition, and the region from which the plants come (Farkas et al., 

 1957 a, b). This is a field that has been very little explored. The changes 

 in the respiratory inhibition of animal tissues with nutrition might not only 

 provide information on the metabolic patterns under various conditions, 

 but be important in the use of the inhibitor to selectively depress the me- 

 tabolism and growth of neoplastic tissues. 



Effects on the Respiratory Quotient 



The effects of an inhibitor on the respiratory quotient (R.Q. = COg form- 

 ed/Og uptake) are often indicative of shifts in metabolic pathways. Let us 

 first consider the theoretical values of the R.Q. for the metabolism of 

 various substrates (see tabulation) in the presence and absence of malonate, 

 assuming that malonate is able to block succinate oxidation completely. 

 Cases in which oxalacetate is formed in the cycle and from noncycle sources 

 must be separated. Summarizing these results, one would expect malonate 

 to increase or decrease the R.Q., depending on the substrate and the nature 

 of the cycle operation. Since a complete block of succinate oxidation would 

 prevent the formation of oxalacetate through the cycle, malonate may 

 shift the pathway from cycle oxalacetate to externally formed oxalacetate, 

 if the latter reaction is possible. If this is so, the R.Q. should rise in every 

 case. 



This prediction is quite consistently borne out experimentally. The R.Q. 

 of rat liver slices rises from 0.72 to 0.77 in the presence of 20 mM malonate, 

 at which concentration the respiration is inhibited 14% (Elliott and Greig, 



