660 METABOLISM 



In all these places by far the greatest proportion of the total creatine- 

 creatinine exists as creatine, which is exactly the reverse of the condi- 

 tion obtaining in the urine of adults, where practically all is excreted as 

 creatinine. The close chemical relationship between creatine and creat- 

 inine, considered along with the above facts regarding their quantitative 

 distribution in the body, indicates that the creatinine of the urine is de- 

 rived from the creatine of the tissues. The question is, How does the 

 creatine come to be converted into creatinine f Such a transformation is 

 probably effected by many of the tissues of the body and certainly by 

 the blood, the active agency in all cases being no doubt an enzyme. That 

 the blood contains such an enzyme is indicated by the fact that creatine 

 is transformed to creatinine by blood serum more quickly than it is 

 when merely dissolved in water. Even heated blood serum possesses 

 some of this power. The liver also probably brings about the transfor- 

 mation, as has been shown by perfusion experiments, and by the fact 

 that in cases of phosphorus or hydrazine poisoning creatine displaces 

 creatinine in the urine. 



The problem therefore narrows itself down to the question of the 

 origin of creatine. In the light of chemical knowledge there are several 

 precursors from which creatine might be formed. One, for example, is 

 arginine, which it will be remembered is guanidine-amino-valerianic acid 

 (see page 640). By oxidation this might become changed into guani- 

 dine-amino-acetic acid, which by methylation would then be changed into 

 creatine. That such a process of methylation may actually occur in the 

 animal body is definitely known, for it happens when such substances as 

 pyridine or naphthalene are given with the food. They appear in the 

 urine as methyl derivatives. The possibility of the derivation of creatine 

 by methylation of arginine is suggested by the result of the injection 

 into ducks of arginine, combined with such substances as paraformalde- 

 hyde (Thompson 59 ). Even in this case however the results are not very 

 convincing. The closely related substance, guanidine-acetic acid, when 

 fed to animals (rabbits) also causes a slight increase in the excretion of 

 creatine (Jaffe), and, it is said, an increase in the creatine content of the 

 muscle. Even in this case, however, by far the largest proportion of the 

 administered guanidine-acetic acid is excreted in the urine unchanged. 



The large percentage of creatine in muscle tissue leads one to expect 

 that some relationship must exist between muscular metabolism and the 

 amount of ereatine present either as such in the muscles or as creatinine 

 in the urine. Regarding the latter point it is definitely established that 

 muscular exercise leads to no increase in the creatinine excretion, al- 

 though it is said that such an increase occurs following a state of tonic 

 muscular contraction. In the light of the fact already stated that there 



