INHIBITOR-STABLE METABOLISM 4:47 



The fraction vj{Vg + v) may vary with the substrate concentration and hence 

 the inhil)ition depends on (S), even though the inhibition is noncompetitive. 

 The total inhibition may either rise or fall as the substrate concentration 

 is increased, depending on the relative values of F,„ and K, for the two en- 

 zymes. It is quite possible that noncompetitive inhibition might be inter- 

 preted as competitive under certain circumstances if correction for the endo- 

 genous metabolism is not made. 



INHIBITOR-STABLE METABOLISM 



An inhibitor will frequently depress a metabolic process in cells or tis- 

 sues incompletely, even though the concentration of the inhibitor is raised 

 to reasonably high levels, at least sufficiently high to produce nearly com- 

 plete inhibition of the enzyme system attacked when that system is isolated 

 from the cell. The interpretation of the inhibitor-stable fraction and the 

 factors that determine its magnitude are often of importance in inhibition 

 studies. The most informative discussion of this phenomenon is that of 

 Commoner (1940) although he was concerned only with cyanide. He ijointed 

 out that changes in the cyanide-stable fraction of respiration during em- 

 bryogenesis and cellular activation could be used to elucidate the metabolic 

 mechanisms and he proposed a simple formulation, which was applied with 

 success to respiratory inhibition in many tissues. The total respiration was 

 assumed to be made up of two fractions, one sensitive and one resistant to 

 cyanide, the latter relatively constant: 



Vt = Vr + «s (9-7) 



(total) (resistant) (sensitive) 



Alteration of substrate concentration or changes in tissue function have 

 marked effects on u, without modifying i\ appreciably. The total respiration 

 thus depends primarily on the level of v, and so the degree of inhibition 

 produced by cyanide also depends on the total rate of respiration. This 

 may be seen by plotting Vf against v^ (Fig. 9-4) where a straight line of 45^ 

 inclination intersecting the v, axis at v^ is obtained. It may be shown that 

 the inhibition of resi)iration is given by: 



it = i (Vslvt) (9-8) 



where i is the inhibition of cytochrome oxidase in the case of cyanide. If 

 the inhibition of the oxidase is complete and v^ is assumed to be 10, the 

 inhibition of the total respiration is 9% when v,. = 1, 33% when Vg = 

 5, 67% when v, = 20, and 83% when v^ = 50. As a consequence, respira- 

 torj^ inhibition need not give a quantitative measure of the inhibition on 

 the enzyme attacked. One must determine the true inhibitor-stable frac- 



