320 2. MALEATE 



at 15 min, 3 hr, and 48 hr after administration (Rogulski, 1960). No changes 

 in blood or liver SH groups occur at any time, but in the kidney there 

 is considerable reduction in both protein and nonprotein SH groups within 

 15 min. In rats on a lactose diet this reduction amounts to as much as 80%. 

 Protein SH is restored at 3 hr but nonprotein SH remains subnormal for 

 much longer. These data also point to the kidney as the primary site of 

 action of maleate, and Rogulski, compared maleate with the mercurials 

 with respect to their actions on the kidney. It is rather unexpected that 

 dimercaprol given intramuscularly is able to abolish the maleate amino- 

 aciduria completely, while glutathione and cysteine are partially effective 

 (Angielski and Rogulski, 1959 b), inasmuch as the rates of reaction of 

 maleate with these thiols do not appear to be sufficiently rapid to account 

 for the inactivation of the maleate in vivo. 



A very interesting comparison of maleate with several other enzyme in- 

 hibitors was made by Angielski et al. (1960 a). Considerable diuresis, glu- 

 cosuria, aminoaciduria, and albuminuria are produced by both maleate 

 and the mercurials, but keto acid excretion is distinctly decreased by the 

 mercurials in contrast to the ketoaciduria seen with maleate. Some of the 

 results are summarized in Table 2-6, from which it is clear that iodoacetate 

 does not share the actions of maleate, whereas malonate produces on the 

 whole a similar urinary picture, although the aminoaciduria is not so severe. 

 One might conclude that maleate may produce its renal effects by inhibition 

 of the cycle, but probably this contributes only to a minor extent, and the 

 primary action is on some system, possibly involving SH groups, responsible 

 for tubular transport and amino acid metabolism. One recalls that the oxi- 

 dation of of-ketoglutarate and the formation of amino acids in kidney mito- 

 chondria are potently inhibited by maleate at concentrations around 1 mM 

 {Table 2-4) and that the dose for maleate aminoaciduria in rats would lead 

 to an over-all concentration of maleate in the body water of around 3-4 mM 

 (Niemiro, 1960). The hypothesis might be entertained that maleate ef- 

 fectively blocks keto acid oxidation, leading to a moderate rise in keto 

 acid excretion, and that part of the keto acid accumulated is aminated to 

 amino acids, which are excreted, this also leading to impairment of the 

 acidification mechanisms in the kidneys. The ammonia required for the 

 amination could come from other amino acids which the kidney normally 

 deaminates and the final result would be an increased urinary amino acid 

 level. On the other hand, the entrance of filtered amino acids into the tu- 

 bular cells or their metabolism might be interfered with in some manner 

 by maleate. It would be interesting to know exactly which amino acids 

 are elevated in the urine during maleate aminoaciduria. 



