532 2. ANALOGS OF ENZYME REACTION COMPONENTS 



in the cat is depressed by thiamine, pyrithiamine, and any of the pyrithia- 

 mine analogs having a hydroxyl group on the pyridinium ring; furthermore, 

 the neuromuscular blocks produced by tubocurarine and decamethonium 

 are antagonized by these compounds (Ngai et al., 1961). In the absence of 

 a hydroxyl group, there is a potentiation of twitch tension. Changes in 

 blood pressure parallel those in twitch tension. These compounds, of course, 

 may bear some relationship to acetylcholine because of the quaternary ni- 

 trogens and other functional groups an appropriate distance away, and it 

 is likely that these acute effects are unrelated to the metabolic aspects of 

 thiamine. It is interesting, however, that oxythiamine is without activity 

 on the neuromuscular junction and respiration, although it causes a fall in 

 blood pressure. No interference by the analogs in the actions of thiamine 

 was reported. Injections of thiamine, thiamine-PP, pyrithiamine, and oxy- 

 thiamine into frogs cause a miosis, which was interpreted as a direct effect 

 on the iris (Ber and Singer- Altbeker, 1961). It is possible that this is me- 

 diated through inhibition of cholinesterase, and it is not necessary to pos- 

 tulate special neural or muscular functions for thiamine. It would be more 

 valuable to study the possible changes in neuro-muscular activity during 

 administration of the analogs chronically and when there are evident motor 

 disturbances. 



Mechanisms of Action and Comparison of Pyrithiamine and Oxythiamine 



Pyrithiamine has been shown to do the following: (1) produce polyneur- 

 itis as in dietary thiamine deficiency, (2) deplete various tissues of thia- 

 mine-PP and increase its renal excretion, (3) inhibit a-keto acid metabolism 

 in vivo, which is reversed by adding thiamine-PP, (4) cause elevation of 

 blood pyruvate, (5) inhibit the phosphorylation of thiamine (thiamine ki- 

 nase), (6) apparently be phosphorylated in the tissues to pyrithiamine-PP, 

 (7) in the diphosphate form inhibit pyruvate decarboxylase, pyruvate oxi- 

 dation, and probably transketolase, and (8) be picked up by the tissues to 

 about the same extent as is thiamine normally. Most of these effects are 

 counteracted by the administration of sufficient thiamine. It is, therefore, 

 not difficult to establish possible sites of pyrithiamine inhibition; most of 

 the reactions to pyrithiamine can be explained on the basis of either a 

 block in thiamine phosphorylation or a direct inhibition of the enzymes 

 utilizing thiamine-PP through its diphosphate ester. If the site were only 

 on the kinase, the fundamental effect would be a depletion of thiamine-PP 

 such as occurs in dietary deficiency, and addition of thiamine-PP to tissue 

 preparations should restore the activity of pyruvate-metabolizing enzymes 

 completely. The reversal is, however, only partial (Gubler, 1961) and by 

 no means as great as in diet-deficient animals. It is thus likely that both 

 mechanisms play a role. The appearance of pyrithiamine mainly in the di- 

 phosphate form in tissues (Rindi and Perri, 1961) also points to the im- 



