EFFECTS ON WHOLE ANIMALS 319 



It is interesting that this triad of glucosuria, phosphaturia, and aminoacid- 

 uria is characteristic of a congenital metabolic defect in man known as the 

 Fanconi syndrome, and in this disease it is common to find rickets resistant 

 to vitamin D. It was felt that an elucidation of the mechanism by which 

 maleate produces these renal effects might give some insight into the 

 metabolic derangement responsible for this disease. 



The aminoaciduria and associated urinary changes produced by maleate 

 have been studied in detail by Angielski and his colleagues in Poland. At 

 a dosage of 300-400 mg/kg, maleate increases the urinary amino acid excre- 

 tion 5- to 10-fold in rats, the maximal effect occurring on the second or 

 third day, recovery to normal levels taking place after a week (Angielski 

 and Kogulski, 1959 a). The aminoaciduria occurs when the rats are on 

 a diet containing milk or lactose, but not on a lactose-free diet. One week 

 on the lactose diet is required to render the rats sensitive to maleate (An- 

 gielski et al., 1959). The degree of aminoaciduria also depends on the vi- 

 tamin intake and tocopherol reduces it. There are actually two phases 

 which may be distinguished. The initial phase of action occurs during 

 the first 2 hr after administration and is characterized by increased urinary 

 excretion of amino acids, keto acids, glucose, and ammonia, and by diuresis. 

 The second phase lasts for several days and is characterized by aminoacid- 

 uria and an even greater diuresis (Angielski et al., 1960 c). The initial phase 

 is independent of the diet, whereas the second phase depends on lactose 

 in the diet. The relationship between maleate aminoaciduria and lactose 

 has been intensively studied, but the mechanism of the dependence has 

 not been elucidated. Handler (1947) stated that rats on a high galactose 

 diet die in a few days and exhibit renal damage and various other changes 

 similar to those produced by maleate. Rats on a galactose diet excrete 

 high levels of the sugar; administration of maleate brings about a rapid 

 and marked fall in galactose excretion (Angielski et al., 1961). On the other 

 hand, rats on a milk diet respond by a rise in galactose excretion. Angielski 

 and his co-workers attribute these effects of maleate to disturbances in 

 galactose metabolism. The rate of conversion of galactose to CO., is believed 

 to be controlled by the epimerization of UDP-galactose. Since this reaction 

 depends on catalytic concentrations of NAD, and is strongly inhibited by 

 NADH, anything that alters the NAD:NADH ratio may affect galactose 

 metabolism. A rise in NADH would reduce galactose oxidation and pre- 

 sumably augment its urinary excretion. Possibly these factors are important 

 in the effects of maleate but there is no direct evidence that maleate alters 

 the NAD: NADH ratio. 



The plasma amino acid level does not rise during maleate aminoaciduria 

 so that the site of action of maleate must be renal (Angielski et al., 1960 b). 

 The ])ossibility that maleate exerts its effects by reacting with thiols was 

 examined by determination of the SH groups in blood, liver, and kidneys 



