TOXICITY or ENZYMES 55 



action is simply explained as being due to establishment of equilibrium ; in some 

 instances, however, the substances produced are of themselves harmful to the 

 enzymes, e. g., alcohol and acetic acid. ('han^f'S in reaction, fixation of the enzyme 

 by cleavage products, and other side reactions may also be at least partly responsi- 

 ble. There is a periodicity in enzyme action which makes quantitative results 

 uncertain.'-'* 



Activation of Enzymes. — Within the cell, the enzymes — at least those that are 

 excreted, such as trypsin and pepsin — exist with few exceptions in an inactive 

 form, tiie zymogen. Their activation appears to take place normally only after 

 they have been discharged from the cell, but after the death of an organ it may 

 result from the decomposition products that are formed. Under physiological 

 conditions this activation appears to he brought about by special activating 

 substances. In the case of the pancreas it is the cnterokinase, which is furnished 

 by the epithelial cells of the intestine. Enterokinase appears to unite with 

 tr3'psinogen to form an active enzyme, which reminds one of the way that comple- 

 ment and the intermediarj- body unite to form hemolytic and bacteriolytic 

 substances.-^ Kinnses, having the same action as enterokinase upon the trypsinogen, 

 are found in various tissues and organs, but generally much less active than the 

 enterokinase. It is verj^ probable that it is through this mechanism that the 

 rate of enzyme action is modified, and perhaps it is a means of defense of the body 

 against its own enzymes; as the prozymes are more resistant to harmful agencies 

 than the enzymes, it also may be a method of storage. The activity of various 

 enzymes is greatly increased by certain more or less specific substances, referred 

 to usually as "coenz^-mes;" thus bile-salts act as co-enzymes for lipase (Loevenhart). 



The Toxicity of Enzymes 



Although present normally in greater or less amounts in all the 

 cells in the body, when artificially isolated and injected directly into 

 animals nearly all enzymes seem to be extremely toxic. As foreign 

 proteins, especially extracts of tissues, are generally more or less 

 toxic, it is difhcult to state how much of the toxicity of a given enzyme- 

 containing solution depends on the enzj^me and how much on the 

 admixt proteins. The following statements are taken at the face value 

 placed on them hy the several investigators quoted, and are subject to 

 discount until the enzymes have been isolated and investigated in a 'pure 

 condition, if such a thing shall ever become possible. 



The first thorough study of the toxicity of enzymes was made by 

 Hildebrandt,^" who found that pepsin, invertase, diastase, emulsin, 

 mja-osin, and rennin were all toxic. The symptoms produced in dogs 

 were trembling, uneasiness, difficulty in walking, and finally coma. 

 The anatomical changes observed were: numerous hemorrhages 

 throughout the body, fatty degeneration of the liver and myocardium, 

 renal congestion, and numerous thromboses. Considerable fever re- 

 sults, and Mayer considers this responsible for the relative harmless- 

 ness of rennin, the action of which is impaired above 40°. That these 

 effects are due to the enzymes themselves rather than to contaminating 



=8 GroU, Nederl. Tijdschr. v. Geneesk., 1918 (1), 1085. 



2^ BayUss and StarUng (Jour, of Physiol., 1905 (32), 129), question the anal- 

 ogy of zymogen-kinase combinations to complement-amboceptor combination. 

 Walker, however, finds evidence that many enzymes consist of a specific ambo- 

 ceptor and a non-specific complement or kinase (Jour, of Physiol., 1906 (33), 

 p. xxi.) 



30 Virchow's Archiv, 1890 (121), 1. 



