Elevation of erythrocyte redox potential linked to galactonate biosynthesis: elimination by Tolrestat.
Alternate pathways of galactose metabolism were explored in erythrocytes from normal subjects and patients with galactose-1-phosphate uridylyltransferase (GALT) deficiency incubated with galactose. Micromolar quantities of galactonate accumulated in both normal and mutant cells linearly with time up to 5 hours and with concentrations of galactose up to 25 mmol/L. Galactitol also was found at levels less than one third of the galactonate level, while galactose-1-phosphate concentrations comparable to those of galactonate were found in galactosemic cells. Concomitant with the formation of these galactose metabolites, the erythrocyte redox potential based on measurement of lactate and pyruvate increased fourfold in both cell types. This was due to a 60% to 72% decrease 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 aldose reductase inhibitor (ARI), Tolrestat (Wyeth Ayerst Research, Princeton, NJ), at 70 micromol/L inhibited the formation of both galactonate and galactitol in both cell types without affecting galactose-1-phosphate, and eliminated the increase in the redox potential as indicated by restoration of pyruvate and lactate levels to the levels obtained before exposure of the cells to galactose. A functioning galactonate pathway is a route of galactose disposal in patients with GALT deficiency, but by altering the cellular redox potential, it may also contribute to galactose toxicity.
Berry
G T
GT
Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, 19104, USA.
Wehrli
S
S
Reynolds
R
R
Palmieri
M
M
Frangos
M
M
Williamson
J R
JR
Segal
S
S
D000328:Adult; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D004376:Galactitol / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013400:Sugar Acids / Q000378:metabolism*; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000172:deficiency / Q000378:metabolism
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D013400:Sugar Acids; C040550:tolrestat; D004376:Galactitol; C012991:galactonic acid; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase