PATHWAYS OF HEPATIC OXALATE SYNTHESIS AND THEIR REGULATION

Important features of hepatic oxalate synthesis remain uncertain despi te its clinical significance. To clarify the terminal steps of the bio synthetic pathway and their modulation, we have examined oxalate and g lyoxylate synthesis in vitro using isolated guinea pig peroxisomes and purified lactate dehydrogenase (LDH). Glycolate was rapidly oxidized to glyoxylate by isolated peroxisomes followed by a slower conversion of glyoxylate to oxalate. The glycolate oxidase (GO)-catalyzed convers ion of glyoxylate to oxalate was strongly inhibited by physiological c oncentrations of glycolate and lactate. In contrast, the LDH-catalyzed conversion of glyoxylate to oxalate was only marginally affected by p hysiological concentrations of lactate and unaffected by physiological glycolate concentrations. This inhibition pattern suggests that LDH, not GO, catalyzes this conversion in vivo. Alanine inhibited oxalate s ynthesis by converting the bulk of the glyoxylate to glycine. On expos ure to high alanine concentrations, however, inhibition was not comple te and peroxisomes were able to convert sufficient glycolate to oxalat e to account for daily endogenous oxalate production. NADH was a poten t inhibitor of oxalate production by LDH by increasing glycolate forma tion from glyoxylate. Glycine was an ineffective source of glyoxylate, and an alkaline pH, a high-glycine concentration, and a prolonged inc ubation time were required to obtain a detectable synthesis. These res ults suggest that oxalate synthesis will be modulated by the metabolic state of the liver and resultant changes in NADH, lactate, and alanin e levels.