ELEVATION OF ERYTHROCYTE REDOX POTENTIAL LINKED TO GALACTONATE BIOSYNTHESIS - ELIMINATION BY TOLRESTAT

Alternate pathways of galactose metabolism were explored in erythrocyt es from normal subjects and patients with galactose-l-phosphate uridyl yltransferase (GALT) deficiency incubated with galactose. Micromolar q uantities of galactonate accumulated in both normal and mutant cells l inearly with time up to 5 hours and with concentrations of galactose u p to 25 mmol/L. Galactitol also was found at levels less than one thir d of the galactonate level, while galactose-l-phosphate concentrations comparable to those of galactonate were found in galactosemic cells. Concomitant with the formation of these galactose metabolites, the ery throcyte redox potential based on measurement of lactate and pyruvate increased fourfold in both cell types. This was due to a 60% to 72% de crease in pyruvate and a 24% to 26% increase in lactate. The oxidation of galactose to galactonate, which is known to generate NADH, is the most likely explanation for the increase in the redox state. The aldos e reductase inhibitor (ARI), Tolrestat (Wyeth Ayerst Research, Princet on, NJ), at 70 mu mol/L inhibited the formation of both galactonate an d galactitol in both cell types without affecting galactose-l-phosphat e, and eliminated the increase in the redox potential as indicated by restoration of pyruvate and lactate levels to the levels obtained befo re exposure of the cells to galactose. A functioning galactonate pathw ay is a route of galactose disposal in patients with GALT deficiency, but by altering the cellular redox potential, it may also contribute t o galactose toxicity. Copyright (C) 1998 by W.B. Saunders Company.