Thiamine Antagonists
Pyrithiamine is a synthetic pyridihe analogue of thiamine. In this compound a -C = Ctakes the place of the -8- in the thiazole group of thiamine. Woolley and White showed that mice develop a thiamine deficiency when pyrithiamine is administered. The process is reversible when sufficient extra thiamine is included in the diet. The symptoms are similar to those produced by a thiamine deficiency in other species. Pyrithiamine, also called "neopyrithiamine," was shown to inhibit the biosynthesis of cocarboxylase by chicken blood but not to lessen the combination of cocarboxylase with the apoenzyme to produce the decarboxylating enzyme. It was also suggested by Woolley and others that pyrithiamine may affect other thiamine systems than cocarboxylase, since ahimals dying of typical thiamindeficiency symptoms as a result of administration of the antagonist showed normal levels of liver cocarboxylase.
The administration of the antagonist oxythiamine (-OR for -NRz in thiamine), however, produced low levels of cocarboxylase. Also, De Caro and workers have demonstrated that the normal increases in heat production and in basal metabolic rate (BMR) in the rat following . glucose administration are inhibited by pyrithiamine but not by oxythiamine. It seems clear that distinct differences exist in the mechanisms of thiamine inhibition by these two antagonists. The 2-n-butyl homologue of thiamine en-butyl group replacing the methyl group on the pyrimidine ring) is a vitamin inhibitor for rats. Emerson and South-wick demonstrated decreased growth rate and certain polyneuritic symptoms in rats fed this compound. The adverse effects were largely obviated by adding thiamine to the diet. These instances are probably examples of the so-called competition reactions. It is thought that the inhibitor molecule may replace the natural vitamin molecule in an enzyme system, or in some other essential metabolic component, and that such a component is not physiologically active.
On the addition of extra, vitamin, the normal system, by mass law action perhaps, may again be formed. An interesting-observation by Gubler and associates regards the action of sorbitol (sugar alcohol of glucose) in rat thiamine deficiency. Rats were made deficient by either thiamine deprivation or by injections of either of the aIitagonists, oxythiamine or pyrithiamine. Half of the deficient rats were fed a basal diet, and the other half this diet containing. 20 per cent sorbitol.
In all cases where the deficiency caused a decrease in growth or in the degree of oxidative decarboxylation of pyruvic or a-ketoglutaric acid, the feeding of the 20 per cent sorbitol diet reversed the growth effect and also resulted in about normal tissue levels of the keto acids. However, increased blood pyruvate was not lowered by sorbitol feeding. The authors suggest that disturbances in pyruvate metabolism may play only a secondary role in the development of thiamine deficiency. It was generally held some years ago that the metabolism of alcohol required thiamine-containing enzymes. Westerfeld and co-workers were especially active in this field. More recent evidence indicates that alcohol ingestion may actually decrease the thiamine requirement.
In thiamine deficiency pyruvic acid accumulates in the body as a result of impaired carbohydrate metabolism (pyruvic acid decarboxylation). If thiamine were required for alcohol metabolism, one would expect a decreased ratp of removal of this molecule from the body in a deficiency of the vitamin. Westerfeld and co-workers found no decreased rate of alcohol metabolism in pigeons during acute thiamine deficiency. Further work by Westerfeld and Doisy demonstrated that in the pigeon alcohol exerts a sparing action on thiamine. When alcohol was substituted isocalorically for part of the carbohydrate of the diet; the thiamine requirement was lessened. The possibility was pointed out that the metabolism of alcohol and carbohydrate together requires less thiamine than the metabolism of carbohydrate alone. Fat and protein likewise exert a thiamine-sparing action.
The neurological findings in alcoholism, it would appear, cannot be explained on the basis of thiamine deficiency resulting from increased demand, but rather as a deficiency resulting simply in lowered intake on the generally inadequate diet of the alcoholic. The specific role of thiamine in relation to neurological findings in thiamine deficiency in animals or in man cannot be stated. In thiamine-deficient rats the intraperitoneal injection of 1 mg of thiamine is followed by a threefold increase in liver total cholesterol and twentyfold elevation of liver neutral glycerides.
Miller and co-workers also report exceedingly high levels of these components following a second injection of the vitamin. Low levels of liver phospholipids also return to normal with
. the first injection. The ratio of free to total cholesterol is high during deficiency, indicating faulty esterification or lack of fatty acids. The ratio falls to below normal following thiamine repletion. Oral thiamine produced similar effects, but the parenteral administration caused a much greater effect on the total cholesterol.
