Inhibition of endogenous oxalate production: biochemical considerations of the roles of glycollate oxidase and lactate dehydrogenase

1. Both the peroxisomal, flavin-linked glycollate oxidase [(S)-2-hydroxy-acid oxidase; EC 1.1.3.15] and the cytosolic, nicotinamide–adenine dinucleotide (NAD)-linked lactate dehydrogenase (l-lactate dehydrogenase; EC 1.1.1.27) are thought to contribute to the formation of oxalate from its immediate precursors, glycollate and glyoxylate, but the relative contributions of each enzyme to endogenous oxalate production is not known. 2. In rat liver homogenates, [14C]oxalate production from labelled glycollate is halved and that from labelled glyoxylate is increased fourfold by the addition of either NAD or NADH. 3. In isolated rat hepatocytes, the 3-hydroxy-1H-pyrrole-2,5-dione derivatives of glycollate, which are specific inhibitors of glycollate oxidase, have a greater effect on glycollate metabolism than on glyoxylate metabolism. 4. These findings are consistent with an important role for lactate dehydrogenase in oxalate formation from glyoxylate. 5. With human and rat liver homogenates and with purified human liver glycollate oxidase and rabbit muscle lactate dehydrogenase, dl-phenyl-lactate (2 mmol/l) completely inhibits glycollate oxidase but has no effect on lactate dehydrogenase. On the other hand, the reduced form of a chemically synthesized, NAD–pyruvate adduct (1 mmol/l) almost completely inhibited lactate dehydrogenase but had no effect on glycollate oxidase. 6. Either alone or in combination, dl-phenyl-lactate and reduced NAD–pyruvate adduct reduce oxalate production from glycollate and glyoxylate in isolated rat hepatocytes, but do not abolish it completely. 7. These findings support a role for another enzyme, probably glycollate dehydrogenase (EC 1.1.99.14), in oxalate production in integrated cell metabolism. 8. In relation to renal oxalate stone disease, these results suggest that the therapeutic inhibition of glycollate oxidase or lactate dehydrogenase would not completely prevent the endogenous formation of oxalate.