EFFECTS ON WHOLE ANIMALS 317 



tions. Fitzhugh and Nelson (1947) fed diets containing various organic acids 

 to rats and found that 0.1-1.5% fumaric acid is without effect on the 

 weight gain. On the other hand, maleic acid at 0.5% minimally inhibits 

 growth (4%), at 1% definitely suppresses growth (20%), and at 1.5% 

 not only markedly reduces growth (41%) but increases the mortality rate 

 so that all the rats die within 2 years. Autopsy examinations showed large 

 and irregularly shaped epithelial cells in the renal tubules, some atrophy 

 of the liver and testes, and less focal calcification of the large arteries. It 

 is possible that the tissue atrophies were due in part to the general state 

 of inanition. No other tissues showed demonstrable changes. 



The effects of maleate on urinary citrate and keto acids have been dis- 

 cussed (Orten and Smith, 1937; Krebs et al., 1938; Krusius, 1940). The 

 studies of El Ha wary (1955) on the effects of SH reagents on the levels of 

 keto acids, ketone bodies, and glucose in the blood of rats are pertinent 

 to the problem of the metabolic disturbances produced by maleate. Ad- 

 ministration of maleate at 420 mg/kg (3.6 miUimoles/kg) intraperitoneally 

 produces the changes given in the accompanying tabulation at 90 min. 



Substances 



Ratio of levels in treated animals 

 to levels in control animals 



Since maleate inhibits the oxidation of pyruvate and a-ketoglutarate, the 

 elevations of the blood levels of these substances might be expected. 

 The greater rise of a-ketoglutarate relative to pyruvate was thought to 

 be due in part to the metabolism of maleate through fumarate, inasmuch 

 as fumarate has been shown to elevate a-ketoglutarate in tissues. If pyru- 

 vate is injected 90 min after the administration of maleate, the blood levels 

 of pyruvate actually increase gradually over 30 min, whereas in normal 

 animals the pyruvate level falls rapidly (see accompanying tabulation). 



