A. D. WELCH AND E. BUEDING 



ordinary circumstances the neurohormone, acetylcholine, responsible 

 for the chemical transmission of nerve impulses at many sites, is de- 

 stroyed promptly, so that the effect of each nerve impulse is very 

 transitory. Partial inhibition of the enzyme which catalyzes the 

 hydrolytic cleavage of acetylcholine permits the accumulation of the 

 neurohormone in higher concentration, a circumstance equivalent in 

 its physiological effects to the injection of acetylcholine at the endings 

 of innumerable cholinergic nerves. Proof that the transitory action of 

 acetylcholine is due to its enzymic destruction and that this enzyme 

 is actually the "site of action" of physostigmine, constituted the first 

 clear-cut demonstration that the primary action of a drug can be based 

 solely on its effect on a single enzyme. It is of considerable practical 

 importance that the rate of hydrolysis of choline esters can be altered 

 by modifying the structure of the choline moiety or of the esterifying 

 acid. Thus, acetyl-j8-methylcholine and carbaminoylcholine have 

 the same pharmacological effect as acetylcholine, but they are slowly 

 or not at all hydrolyzed by choline esterase. 



Other examples of drugs and poisons, the primary action of 

 which involves enzyme systems, are neostigmine, a compound related 

 to physostigmine, ionizable cyanides, and such vitamins as thiamin, 

 riboflavin, and niacin. However, there is strong presumptive evidence 

 for the involvement of enzyme systems in the action of various other 

 drugs and poisons. 



Quastel et al. (26) have gtttempted to explain the mechanism 

 of action of narcotics in terms of their effects on the respiration of brain 

 tissue and on isolated enzyme systems. Various drugs which produce 

 anesthesia (barbiturates, chlorobutanol, and ether) were shown to 

 inhibit reversibly the oxygen consumption of the cortex in vitro. Oxi- 

 dation of glucose, lactate, or pyruvate is inhibited to a larger degree 

 than the oxidation of either succinate or glutamate, while the anerobic 

 utilization of glucose by the brain tissue is inhibited only slightly. In 

 continuation of this work, the effect of chlorobutanol on several 

 enzyme systems involved in the oxidation of glucose was examined by 

 Michaelis and Quastel (22). Since the activity of various dehydro- 

 genases, cozymase, Straub's flavoprotein ("diaphorase"), or cyto- 

 chrome oxidase is not decreased by chlorobutanol, in concentrations 

 which inhibit glucose oxidation in the brain, it was concluded that the 

 narcotic inhibits an as yet unidentified respiratory enzyme system. 



402 



