Apeil 9, 1909] 



SCIENCE 



589 



atinin output, have a more immediate interest. 

 Clinical investigators seem to forget that in 

 these experiments of nature one rarely deals 

 with simple conditions where a single organ, 

 such as liver or muscle, is independently in- 

 volved. 



To attempt to formulate a theory of creatin 

 and creatinin metabolism at this time would, 

 in my judgment, be premature. It may, how- 

 ever, help us to crystallize the discussion by 

 outlining some salient points of view. I think 

 it will be agreed that the muscle plays a com- 

 paratively small part in the formation of cre- 

 atinin. Let us assume for the moment that 

 creatin represents a metabolism product orig- 

 inating in various organs, perhaps notably in 

 the liver. It is transported about and espe- 

 cially deposited in the muscle in some non- 

 difEusible combination. Most of it will be 

 destroyed in ways that may be facilitated by 

 enzymes. Here again it appears likely that 

 the liver plays a prominent role. A part may 

 be changed to creatinin, which may in turn 

 be either destroyed or excreted. For this part 

 of our hypothesis the evidence is most imcer- 

 tain. Creatinin behaves as a waste product; 

 it is decomposed with greater difficulty than is 

 creatin, and it is eliminated more readily. 

 But whether it represents a real end product, 

 or like uric acid is an intermediary product, 

 the output of which we associate with a bal- 

 ance between productive and destructive proc- 

 esses, can not yet be determined. At any rate, 

 unchanged creatinin is promptly excreted and 

 is nowhere to be found in detectable quantities 

 in the organism. When the functional activi- 

 ties of the body are depressed or stimulated 

 corresponding variations in creatin production 

 and destruction may go on (van Hoogenhuyze 

 and Verploegh, '08). So long as effective 

 katabolic powers are maintained, the varia- 

 tions in creatinin output will be slight at most 

 and: in correspondence with the physiological 

 state. Any excess of creatinin will represent 

 only a fraction of the undestroyed increase 

 in creatin. From this point of view the 

 muscles would furnish creatin only as physio- 

 logically active organs and not as an incident 

 of their contraction. The energy for contrac- 

 tion comes from quite different sources. 



When, however, the tissues are drawn upon 

 for supplies, as in hunger or cachexia, creatin 

 is liberated by the disintegrating muscle; and 

 owing to the lowered effectiveness of the 

 katabolic organ, let us say the liver, the creatin 

 now escapes destruction and is eliminated as 

 such. In other words, in normal metabolism 

 creatin is continually produced and destroyed, 

 or converted to creatinin which is speedily 

 eliminated. In starvation preformed creatin 

 is liberated; and neglecting to experience the 

 customary destruction, it escapes unchanged. 

 Here creatin is a product both of metabolism 

 and of tissue resolution. 



It is an easy task to offer objections to the 

 outline just presented. A primary source of 

 difficulty lies in the failure of most investi- 

 gators to demonstrate that creatin, introduced 

 into the circulation, in any way affects the out- 

 put of creatinin. I have already spoken of 

 this fact. Perhaps we have not yet succeeded 

 in imitating the conditions of equilibrium 

 which pertain in normal metabolism. JVTel- 

 lanby has protested against the conventional 

 interpretation and lays primary emphasis upon 

 creatimin, which he regards as being continu- 

 ally formed in the liver from substances 

 brought to it. In the developing muscle this 

 is changed to creatin and stored as such until 

 a saturation point is reached, whereupon cre- 

 atinin is continuously excreted. Mellanby 

 urges that from a chemical point of view it is 

 easier to assume the preliminary production 

 of a cyclic structure like creatinin and its sub- 

 sequent conversion to creatin, than the reverse 

 process. Creatin is neutral and innocuous, 

 and not likely to be changed to the strongly 

 basic creatinin. The argument is teleological 

 and not convincing; and to the liver are as- 

 cribed functions for which there is little evi- 

 dence under either theory. 



More profitable than this hypothetical dis- 

 cussion will be a consideration of some of the 

 investigations which are immediately de- 

 manded. At the outset we need to know more 

 definitely about the possible distribution of 

 creatin in the tissues and blood; and above all, 

 whether the creatin content of the muscle is 

 normally a constant, as some maintain, or 

 subjected to variations incident to activity. 



