ANALOGS OF THIAMINE 533 



portance of direct a-keto acid enzyme inhibition. The rapidity with which 

 pyrithiamine exerts its toxicity (Eusebi and Cerecedo, 1949), relative to 

 dietary deficiency, would indicate an effect other than a block of thiamine- 

 PP synthesis. The exact role of thiamine kinase inhibition cannot be eval- 

 uated at this time. 



When we turn to oxythiamine the problem becomes more complex. The 

 major differences from the actions of pyrithiamine may be summarized as 

 follows: (1) typical polyneuritis is not produced, (2) it is not as effective 

 in reducing tissue thiamine-PP levels, particularly in the brain, (3) it does 

 not produce a significant depression of pyruvate oxidation in the brain in 

 vivo, (4) inhibition of thiamine kinase is slight or absent, and (5) its toxic 

 effects are more readily overcome by thiamine. The most obvious explana- 

 tion would be that oxythiamine has generally the same actions as pyrithia- 

 mine in most tissues but for some reason does not interfere readily with 

 thiamine function in the nervous system. Failure to penetrate into nerve 

 tissue would adequately account for this but there is no direct evidence for 

 this, unless the failure of oxythiamine to affect the membrane potentials 

 of frog nerve, although pyrithiamine is effective, is interpreted in this way. 

 One aspect that has usually not been considered is the metabolism of these 

 analogs in the tissues, although Cerecedo et al. (1951) felt that oxythiamine 

 is more rapidly metabolized than pyrithiamine. Just as in resistant bacteria, 

 resistant tissues may contain a thiaminase-like enzyme capable of destroy- 

 ing the analog, and it is possible that a particular tissue can inactivate one 

 of these analogs more than the other. 



If the major pathway of thiamine in animal tissues is simply (1 ) the trans- 

 port of thiamine into the cells, (2) its phosphorylation, and (3) the com- 

 bination of the thiamine-PP with the apoenzymes, the analogs must act on 

 one of these steps. Pyrithiamine inhibits steps (2) and (3), while oxythia- 

 mine affects only (3). No examination of interference with transport systems 

 has been reported but this should be done. The question of whether thiamine 

 has actions additional to its function in cc-cleavage, especially in nervous 

 tissue, must arise (Woolley and Merrifield, 1952; Gubler, 1961), but I doubt 

 if the evidence from the use of analogs is sufficient at the present time to 

 imply mechanisms other than on the established systems. One cannot judge 

 the state of a tissue function from changes in blood pyruvate (which re- 

 flects changes throughout the whole animal and perhaps particularly in the 

 liver); if central nervous system effects are to be evaluated, alterations in 

 the metabolism in the nerve cells must be determined. Also one must al- 

 ways consider the relationship between cell function and thiamine-PP level. 

 To what degree must thiamine-PP in the brain fall before symptoms occur? 

 This has often been judged by experiments in diet-deficient animals, but 

 in analog-treated animals it is not necessary that thiamine-PP levels be 

 reduced to the same degree to obtain the same functional disturbances. 



