PHARMACOLOGY 



suggested, therefore, that the term "detoxication" be reserved only for 

 those metabolic reactions which result in the formation of substances 

 less toxic than the compounds from which they are derived, and to 

 apply the term "metabolic alteration" to all changes which foreign 

 compounds undergo in the organism. Metabolic alteration will usually 

 be accomplished by means of oxidation, reduction, hydrolysis, or 

 conjugation. 



It is not inconceivable that reactions resulting in detoxication 

 may be favorably influenced and, conversely, that reactions resulting 

 in increased toxicity can be inhibited. In order to investigate these 

 hypotheses, which could have considerable practical significance, 

 biological systems concerned with the metabolic alteration of foreign 

 compounds should be studied. 



The transitory action of certain drugs in the body, as a result 

 of their rapid alteration, is often disadvantageous, and in some cases 

 the inhibition of such inactivation-reactions may be useful, as has been 

 shown for the inhibition of choline esterase by physostigmine or neo- 

 stigmine. With other transiently active compounds an inhibition of 

 inactivation may be difficult to accomplish, because of their suscepti- 

 bility to several enzyme systems which act on a variety of substrates. 

 Thus, epinephrine is oxidized by the lactic or malic dehydrogenase 

 systems, by cytochrome C (10), by amine oxidase (9), and probably 

 by other enzyme systems. 



Richter (27) postulated that epinephrine is inactivated in the 

 body by conjugation with sulfate, a theory based partly on the observa- 

 tion that epinephrine increases the excretion of organic sulfate. How- 

 ever, the quantity of organic sulfate excreted after epinephrine ad- 

 ministration is much greater than can be accounted for by conjugation 

 with the drug administered (7). Since epinephrine decreases the 

 formation of glucuronic acid by liver slices (16), it is possible that the 

 hormone stimulates the formation of conjugated sulfates and decreases 

 the production of glucuronates without itself extensively participating 

 in the formation of the excreted organic sulfate. 



While many foreign substances are enzymically oxidized in 

 the body, other compounds accept hydrogen as a result of enzymic 

 catalysis. In this manner trinitrotoluene (TNT) is partially reduced 

 in the body by flavoproteins (4). It is interesting to note that one 

 product of the reduction, hydroxylaminodinitrotoluene, is more toxic 



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