510 ROSENBLOOM AND KAHN 



That this is the path of the change is further confirmed by the fact 

 that the feeding of hydroquinon pyruvic acid (IV) augments the amount 

 of alkapton excreted in the urine. 



In 1892, Gamier and Voirin advanced the hypothesis that the disturb- 

 ance in alkaptonurics is a failure to break down the hornogentisic mole- 

 cule, According to their view, this molecule is produced in the normal 

 metabolism of protein, but whereas in the normal individual the molecule 

 is broken down, in the alkaptonuric the homogentisic acid is excreted 

 unchanged. To this view the modern trend of opinion seems to tend. 

 The arguments in support of it are as follows: 



1. Were homogentisic acid an abnormal intermediary product, the 

 body would use measures to protect itself against it. This acid is not 

 excreted combined with sulphuric or glycuronic acid, but is excreted as its 

 ammonium salt unchanged in the urine. With an abnormal constituent 

 like gentisic acid, its homologue, Likhatscheff, has shown that it is excreted 

 when administered as the aromatic sulphate. 



2. The administration of homogentisic acid to normal individuals 

 in fairly large quantities fails to cause its overflow into the urine. That 

 is, it is completely broken down. If very large quantities are administered 

 traces of it are found in the urine (Embden). 



3. That the power to catabolize homogentisic acid is completely lost 

 in the alkaptonuric, and not simply overtaxed, is shown by the fact that not 

 part but all of the tyrosin and phenylalanin fraction of the broken down 

 protein is changed to alkapton and is excreted as such in the urine. 



Knoop and Grutterink and van den Bergh have, however, raised cer- 

 tain objections to the above hypothesis, and it is rather difficult to pass 

 them by without some discussion. 



It is known that in dogs the power to catabolize homogentisic acid is 

 limited. Knoop, therefore, administered to dogs phenyl-a-lactic acid, 

 which in alkaptonurics increases the output of alkapton. In the dogs no 

 excretion of the alkapton was observed. 



Similarly in individuals suffering from hepatic disease and diabetes, 

 the Dutch authors found an inability properly to burn homogentisic acid. 

 To such subjects tney administered tyrosin in doses of 10 to 15 grams. 

 No appearance of alkapton in the urine was observed after such tyrosin 

 administration. 



Dakin's experiments, referred to later, also seem to indicate that forma- 

 tion of homogentisic acid is always pathological. 



It would seem, as Garrod points out, that "the most serious objection 

 which can be raised to the view that homogentisic acid is an abnormal 

 product, peculiar to alkaptonurics, is that such a view involves the as- 

 sumption that the alkaptonuric, who alone has the power of forming homo- 

 gentisic acid, is also exceptional in having no power of destroying it when 

 formed." 



