Studies on the physiological functions of thiamine. I. The effects of thiamine deficiency and thiamine antagonists on the oxidation of alpha-keto acids by rat tissues.

Although thiamine has been known and studied for many years, there is still much we do not know about its physiological functions and mechanism of action in biological systems, particularly in animal tissues. Earlier workers have shown that thiamine diphosphate (cocarboxylase) functions as a coenzyme in the metabolism of pyruvate and a-ketoglutarate (l-9). However, the question regarding the importance of the disturbances in a-keto acid metabolism as contributing factors to the symptoms of thiamine deficiency has never been satisfactorily answered. Use has been made of the thiamine antagonists, pyrithiamine and oxythiamine, in animal experiments in order to elucidate the functions and mode of action of thiamine (10-15). These studies suggest that pyrithiamine and oxythiamine antagonize different reactions and, hence, elicit different deficiency symptoms. In view of the differences in site or mode of action or both, of these two thiamine antagonists, it seemed of considerable interest to study in detail the activity levels and characteristics of thiamine-dependent enzyme systems in the tissues of animals in which thiamine deficiency had been induced by various methods. In this study thiamine deficiency was induced in rats by thiamine deprivation and by the administration of pyrithiamine and oxythiamine, and measurements have been made of the rates of oxidative decarboxylation of various cy-keto acids by liver mitochondria and brain, kidney, and heart homogenates from normal and deficient rats. A preliminary report of some of this work has been published (16).