The Trapping of Uridine Phosphates by d‐Galactosamine,d‐Glucosamine, and 2‐Deoxy‐d‐galactose: A Study on the Mechanism of Galactosamine Hepatitis

Abstract

The effects of d‐galactosamine,d‐glucosamine, and 2‐deoxy‐d‐galactose on rat liver uracil nucleotides were studied in vivo. Enzymic and isotope dilution analyses of the UDP‐sugars and of uridine phosphates revealed three major, related changes: an accumulation of the respective UDP‐sugar derivatives, a marked decrease of UTP, UDP, and UMP, and a subsequent increase of the sum of hepatic uracil nucleotides. The decrease of uridine phosphates was accompanied by diminished contents of UDPG and UDP‐galactose. UMP of total liver RNA was not altered significantly. Inhibition of uridylate synthesis by use of 6‐azauridine resulted in a suppression of the d‐galactosamine‐induced stimulation of uridine phosphate synthesis and of the increase in total acid soluble uracil nucleotides. The trapping of uridine phosphates by formation of UDP‐sugar derivatives was most pronounced and most prolonged after administration of d‐galactosamine. The uridine phosphate content was lowered to less than 10% of normal within three hours, while the sum of uracil nucleotides increased by 0.35 μmole x g liver−1 x hour−1, from an initial value of 1.24 μmole/g. The quantitative analysis of the time dependent changes of UDP‐hexosamines, UDP‐N‐acetylhexosamines, UDPG, and UDP‐galactose revealed a pronounced alteration by d‐galactosamine of the UDP‐sugar pattern. Corresponding changes in the distribution of liver uracil nucleotides were obtained after administration of d‐glucosamine and 2‐deoxy‐d‐galactose. Both, however, are ineffective in provoking hepatitis. In contrast to d‐galactosamine,d‐glucosamine and 2‐deoxy‐d‐galactose do not lead to the formation of UDP‐hexosamines; furthermore they are less efficient in trapping uridine phosphates in vivo. These observations contribute to an understanding of the orotate‐mediated prevention of the galactosamine‐induced liver damage, and of the role of pyrimidine nucleotides in this experimental hepatitis.