Xylitol Metabolism in Perfused Rat Liver

Xylitol metabolism and its interaction with lactate metabolism has been investigated in perfused livers from fasted rats. Xylitol (5 mM) served as a strong reductant for cytosolic NAD systems as shown by increased ratios of lactate to pyruvate, a-glycerophosphate to dihydroxyacetone-P, and triose phosphates to 3-P-glycerate. The mitochondrial NAD system, as monitored by changes of the fl-hydroxybutyrate to acetoacetate ratio, was less affected, particularly when xylitol was added in the presence of lactate, suggesting a limitation in the rate of transport of NADH from cytosol to mitochondria. Xylitol also caused an increased reduction of bound NAD as determined analytically and by increased pyridine nucleotide fluorescence measured by surface fluorometry. The latter technique showed that half-maximum reduction was obtained with 0.4 UIM xylitol, suggesting that xylitol was metabolized principally to D-XylUlOse via the low K, cytosolic NAD-linked xylitol dehydrogenase. In the perfused liver xylitol was converted mainly to glucose, after phosphorylation of D-xylulose to D-xylulose-5-P and metabolism via the pentose phosphate pathway. Lactate uptake and conversion to glucose were strongly inhibited by xylitol. This effect was interpreted as resulting from the increased cytosolic NADH: NAD ratio which caused pyruvate levels to fall. An observed decrease of acetyl coenzyme A levels may also contribute to diminished flux through pyruvate carboxylase. Xylitol uptake was less affected by the presence of lactate, presumably because of the lower midpotential of NAD-xylitol dehydrogenase ( -236 mvolts) compared with that of lactate dehydrogenase (-216 mvolts). Ketone body production from endogenous fatty acids was inhibited equally by lactate and xylitol. The production of ketone bodies from added oleic acid was marginally inhibited