Metabolism of 2‐Deoxy‐ D ‐galactose in Liver Induces Phosphate and Uridylate Trapping

The metabolites of 2‐deoxy‐D‐galactose were quantitatively determined in liver and in various tissues of the rat. After intraperitoneal administration of 2‐deoxy‐D‐[1‐14C]galactose in a dose of 1 mmol/kg the liver was the predominant organ metabolizing this galactose analog. 2‐Deoxy‐D‐galactose 1‐phosphate and UDP‐2‐deoxy‐D‐galactose were the major hepatic metabolites and after 3 h comprised 78% and 20% of the total radioactivity in liver, respectively; UDP‐2‐deoxy‐D‐glucose amounted to 0.7%. Liver was the only tissue in which substantial formation of UDP‐2‐deoxy‐D‐hexoses was observed. The synthesis of UDP‐2‐deoxy‐D‐galactose was shown to be catalyzed by UDP‐glucose:galactose‐1‐phosphate uridylyltransferase. The low affinity of this enzyme for 2‐deoxy‐D‐galactose 1‐phosphate explained the accumulation of this substrate analog to levels as high as 14 mmol/kg liver. Enzymatic analysis of alkaline ethanol extracts showed a marked fall of the hepatic Pi content during the period of rapid 2‐deoxy‐D‐galactose 1‐phosphate formation. The trapping of Pi was associated with a loss of ATP and a lowering of the adenylate energy charge. The formation of UDP‐2‐deoxy‐D‐galactose occurred only after high levels of 2‐deoxy‐D‐galactose 1‐phosphate had been attained. The limited epimerization of UDP‐2‐deoxy‐D‐galactose to UDP‐2‐deoxy‐D‐glucose led to an accumulation of the former deoxy‐sugar nucleotide. The trapping of uridylate in the form of UDP‐2‐deoxy‐D‐galactose was accompanied by a transient decrease in the hepatic contents of UTP, UDP‐glucose, and UDP‐galactose. The administration of 2‐deoxy‐D‐galactose together with uridine or orotate completely prevented the depression of UTP. The accumulation of 2‐deoxy‐D‐galactose 1‐phosphate and the associated depression of Pi, in the absence of UTP deficiency, represent a state analogous to that induced by galactose in uridylyltransferase‐deficient cells and tissues and may serve as a biochemical model in the study of the cellular injury in galactosemia.