Enzymes as Primary Targets of Drugs

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Abstract
The importance of studies wherein cholinesterase inhibition cannot be related to pharmacological action of the drug should be emphasized. This lack of correlation may be an artifact and certainly calls for a study of the reasons for the finding. A compound which is a very active cholinesterase inhibitor in vitro or in vivo may fail to affect a given system in vivo. This does not allow one to say that cholinesterase has no role in the functioning of the system in vivo. The role of cholinesterase in the in vivo situation can be better assessed if the fate of the cholinesterase inhibitor in vivo is known[long dash]i.e., its absorption, distribution, excretion, and metabolism. The essential question: is the cholinesterase of the in vivo system inhibited by the inhibitor at the time when the system is still functioning normally? There are several ways to study this. One of the simplest is to remove parts of the in vivo system and assay for cholinesterase activity in vitro. This approach has many pitfalls since the process of isolating the system for a study of enzyme activity may allow an exposure of enzyme to inhibitor that would not occur in vivo. Histochemical techniques might therefore be more desirable if one could be certain that artifacts" occurring during fixation and staining did not change the relation which existed in vivo between the cholinesterase and inhibitor. At present, the histochemical methods seem to be adequate for these purposes and might be used in deciding whether cholinesterase inhibition could or could not reasonably explain a given in vivo effect. One other point of interest is the apparent excess of cholinesterase at most of its sites of function. The fact that inhibition of the enzyme can be proved to occur in vivo without affecting a given physiological function still may not answer the question of the role of cholinesterase in this function. If the enzyme is present in 100-fold excess, then any inhibition less than 100% will fail to affect function. Histochemical techniques can seldom distinguish between 90 and 100% inhibition of enzyme activity. It is to be hoped that newer techniques, including the use of radioisotopes, may finally permit differentiation between an inhibition that is related to drug action and one which is not. Certainly both alternatives are important.