The Sequence of Changes in the Biosynthesis of Sulfated Glycosaminoglycans in Acute, Experimental Liver Disease

Summary: The incorporation of [35S]sulfate into total and specific glycosaminoglycans of the liver of rats injured acutely by a singie intraperitoneal dose of either jD-galactosamine (700 and 350 mg/kg body weight, respectively) or thioacetamide (100 mg/kg body weight) was studied in vivo and in liver slices. Regardless of the chemical nature of the hepatotoxic agent and its mechanism of action the incorporation of isotope in vivo is changed biphasically: a rapidly occurring and strong Inhibition is followed by pronounced elevation in later stages of injury. In contrast to the dose-dependent Inhibition of heparan sulfate formation the production of chondroitin sulfate and dermatan sulfate is only slightly and for a rather short period of time diminished. The synthesis of the latter glycosamino-glycans is stimulated 3 to 4 fold 8 to 24 h after onset of liver damage, fhat of heparan sulfate about 2 fold. Impaired synthesis of heparan sulfate occurs before the elevation of the activities of aspartate aminotransferase, alanine aminotransferase, and leucine arylamidase in serum. The specific radioactivity of 3'-phosphoadenosine-5'-phospho-sulfate remains nearly constant in galactosamine-damaged livers. Similar time-dependent changes of [3S S]sulfate incorporation into heparan sulfate, chondroitin sulfate and dermatan sulfate were measured in slices from livers injured in vivo for various times with-D-galactosamine or thioacetamide. Neither serum from normal nor galactos-aniine-treated rats influences the total amount and the pattern of glycosaminoglycans synthesized in normal or injured liver slices. Hepatic glycosaminoglycan formation of 3.5 and 33 months old rats responds quantitatively an