588 GASTRO-INTESTINAL "AUTOINTOXICATION" 



and phenylalanine, homogentisic acid is not an intermediary product, 

 and Dakin states that the alkaptonuric can destroy simple derivatives 

 of phenylalanine and tyrosine, provided their structure is such that the 

 formation of substances of the type of homogentisic acid is precluded 

 He believes that in alkaptonuria there is abnormal formation of 

 homogentisic acid as well as a failure to destroy it when formed. On 

 the other hand, Abderhalden^^ has been able to cause the appearance 

 in the urine of homogentisic acid in a normal individual by feeding 

 large amounts of tyrosine, which is in favor of the view that it is a normal 

 intermediary in tyrosine catabolism.'^'* In any case the administration 

 of tyrosine or phenylalanine, or of tyrosine-rich foods — i. e., proteins — 

 causes a marked increase in the amount of homogentisic acid eliminated 

 in the urine; indeed, this increase is almost quantitative. Normal 

 individuals when given these substances in moderate amounts, or 

 homogentisic acid itself, destroy them completely, so that the latter 

 does not appear at all in the urine. ''^ If alkaptonurics are kept with- 

 out protein food for some time, the elimination of alkaptonuric 

 acid goes on, although in diminished amounts, indicating that the 

 aromatic amino-acids formed in tissue catabolism also fail to be de- 

 stroyed and, therefore, appear in the urine as these derivatives. 

 Since gentisic acid, 



OH 

 /^— COOH, 

 HO 



when given by mouth, is also eliminated unchanged by alkaptonurics, 

 although completely destroyed by normal individuals, it seems evident 

 that the difficulty in metabolism affects the benzene ring itself and 

 does not depend upon the character of the side-chain. Normal organ- 

 isms seem to be capable of destroying such aromatic compounds as 

 pass through a stage of homogentisic acid in being oxidized, which 

 indicates that the benzene ring can be broken up only when oxidized 

 in this particular manner (the 2, 5 position) ; the alkaptonuric differs 

 in being unable to break up even this form (Falta). According to 

 Garrod'^'^ the conversion of tyrosine and phenjdalanine into homogen- 

 tisic acid is so complete that the ratio of homogentisic acid to nitro- 

 gen is constant and the same in all cases. Frommhcrz and Her- 

 manns'^ advance the suggestion that normal oxidation of tlic aromatic 

 radicals may take place by two routes, one b}' way of homogentisic 

 acid, the other by way of the 3-4 dioxy-derivatives (i. e., pyrocate- 

 chin), since such derivatives can be readilj^ oxidized in the metabolism 



'3 Zeit. physiol. Chem., 1912 (77), 454. 



'\Katsch (Deut. Arch. klin. Med., 1918 (127), 210) believes that homogentisic 

 acid is converted into acetone. 



'^ Gross states that normal serum destroys homogentisic acid, which property 

 is lacking in the serum of alkai)tonurics (Hiochem. Zeit., 1914 (til), 1C5). 



" Garrod and Clarke, Biochem. Zeit., 1907 (2), 217. 



" Zeit. physiol. Chem., 1914 (91), 194. 



