Studies on the Mechanism of Galactosamine Hepatitis: Accumulation of Galactosamine‐1‐Phosphate and its Inhibition of UDP‐Glucose Pyrophosphorylase

Abstract

d‐Galactosamine has been shown to produce a liver damage closely related to human viral hepatitis. d‐Galactosamine‐1‐phosphate and UDP‐galactosamine were identified as the predominant early metabolites of galactosamine in rat liver. The conversion of galactosamine‐1‐phosphate to UDP‐galactosamine is shown to be catalyzed by UDP‐glucose: α‐d‐galactose‐1‐phosphate uridylyltransferase. The low affinity of this enzyme for galactosamine‐1‐phosphate explains in part the high levels of this compound found in galactosamine treated livers. Under these conditions galactosamine‐1‐phosphate accumulation is enhanced by the strongly reduced levels of UDPG. Galactosamine‐1‐phosphate inhibits the UDPG‐pyrophosphorylase reaction, the type of inhibition being mainly competitive with glucose‐1‐phosphate. In the presence of the concentrations of galactosamine‐1‐phosphate and glucose‐1‐phosphate found in vivo after galactosamine treatment, UDPG‐pyrophosphorylases from rat and calf liver are strongly inhibited in vitro. By these mechanisms galactosamine‐1‐phosphate counteracts its own conversion to UDP‐galactosamine. The influence of the strongly diminished UDPG levels on the UDPG‐linked syntheses of glycogen, heteropolysaccharides and glucuronides as well as the trapping of uridine phosphates by formation of UDP‐hexosamines may play an important role in the induction of galactosamine hepatitis.