PSEUDO-IRREVERSIBLE INHIBITION 



81 



When a pseudo-irreversible or irreversible inhibitor is introduced into 

 an animal intravenously (to ensure relatively rapid and uniform distribution 

 throughout the body), the susceptible enzyme will be inhibited to different 

 degrees in the various tissues; those tissues possessing the smallest amount 

 of enzyme vrill be inhibited most potently. It must be assumed that the in- 

 hibitor enters each tissue to approximately the same degree. This type of 

 effect is in distinct contrast to the behavior of readily reversible inhibitors, 

 where the inhibition in any tissue depends only on the concentration of 

 inhibitor and not at all on the amount of enzyme present; if the inhibitor 

 entered each tissue equally, the inhibition in each would be the same, assum- 

 ing that the enzyme had the same properties and environment in every 

 tissue. It was suggested by Potter et al., (1952) that the principle of 

 enzyme titration might be applied to chemotherapy. Cells that contain 

 the least amount of the susceptible enzyme are most readily inhibited and 

 perhaps most easily killed; for example, tumor tissue succinoxidase was 

 inhibited completely by an amount of antimycin that had no effect on heart 

 succinoxidase, and only minimal effects on the enzyme from kidney, liver, 

 brain, and muscle were observed, simply because there was less of the 

 enzyme in the tumor tissue. Complications naturally arise: the effects of 

 binding to blood components, the different blood supplies to various tissues 

 so that the inhibitor is not equally distributed, the different permeabilities 

 of cells to the inhibitor, and the fact that an enzyme may exhibit some- 

 what different kinetic parameters in each tissue. However, it does represent 

 one intelligent and directed approach to chemotherapy, which, if pursued 

 intently, might well lead to the development of useful drugs. 



Finally, it may be remarked that figures given for the per cent inhibition 

 of enzymes by inhibitors of this type mean very little, unless the amount 

 of enzyme present is also stated (Ackermann and Potter, 1949). The inhi- 

 bitions bear no necessary relation to the potency of the inhibitor or the 

 Ki and cannot be compared on any quantitative basis with inhibitions pro- 

 duced by readily dissociable inhibitors. For example, let us assume (E,) = 

 10-^ M and we compare four inhibitors with different K-&. The tabulation 

 below shows the concentrations necessary to produce a standard inhibition 

 and it is evident that these concentrations do not indicate quantitatively 



