Synthesis of Hepatic Glycosaminoglycans in the Early Stages of Galactosamine Hepatitis: A Rapid Decline of Heparan Sulfate is Followed by Elevation of Chondroitin Sulfate and Dermatan Sulfate

Abstract

Summary: Administration of a single dose of jD-galactosamine to rats causes time-dependent, biphasic changes of total glycosaminoglycan synthesis in liver. A rapidly occurring inhibition is followed by a significantly enhanced 0> 2 fold) production of 35 S-labeled glycosaminoglycans in later stages of injury. Degree and duration of the inhibitory phase are dose-dependent; 50% inhibition is reached at 80 mg/kg and maximum inhibition (nearly 80%) at about 300 mg/kg body weight 2 h after injection of Z)-galactosamine.The hepatötoxin impairs preferentially the production of heparan sulfate, whereas that of chondroitin sulfate and dermatan sulfate is diminished only slightly and for a rather short period of time. The synthesis of the latter, however, is more stimulated than that of heparan sulfate in later stages of injury.The specific radioactivity of 35 S-labeled 3'-phosphoadenosine-5'-phosphosulfate (PAPS) did not change significantly during the course of acute liver damage.Glycosaminoglycan synthesis in regenerating liver was nearly unaffected by D-galactosamine. Uridine at the dose applied partially reversed Agdactosamine-inhibited synthesis of proteoheparan sulfate.In accordance with the labeling studies the content of glucosamine^containing glycosaminoglycans in treated liver decreased, whereas that of galactosamine-cöntainiiig glycosaminoglycans slightly increased, resulting in a nearly 50% reduction of the glucosamine/galactosamine ratio 5 h after administration of Z)-galactosamine. Ion exchange Chromatographie studies of 35 S4abeled specific types of glycosaminoglycans from normal and galactosamine-injured liver revealed only minor structural differences. Synthese der Leberglykosaminoglykane in den Frühstadien der Galaktosamin-Hepatitis: Einer raschen Erniedrigung des Heparansulfates folgt eine Erhöhung von Chondroitinsulfat und DermatansulfatZusammenfassung: Eine Einzeldpsis von D-Galaktösamin erzeugt in der Rattenleber zeitabhängige, biphasische Veränderungen der Glykosaminoglykansynthese. Eine sofort eintretende Hemmung wird gefolgt von einer signifikant erhöhten (über 2fäch) Produktion 35 S-marJaerter Glykosaminoglykane in späteren Stadien der Schädigung. Grad und Dauer der inhibitorischen Phase sind dosisabhängig; 50% der Hemmung tritt bei 80 mg/kg und maximale Hemmung (nahezu 80%) bei etwa 300 mg/kg Körpergewicht 2 Stunden nach Verabreichung von £-Galaktosamin ein. Das hepatotöxische Z^Gdaktosamin beeinträchtigt vorzugsweise die Produktion von Heparansulfat, wohingegen die Synthese von Chondroitinsulfat und Dermatansulfat nur geringgradig und für einen kurzen Zeitraum vermindert ist. Die Bildung der letztgenannten Glykosaminoglykane wird jedoch in späteren Stadien der Schädigung stärker als die von Heparansulfat stimuliert.Die spezifische Radioaktivität von 35

Preventive Effects of Acute Inflammation on Liver Cell Necrosis and Inhibition of Heparan Sulphate Synthesis in Hepatocytes

“…The Inhibition occurs much earlier than any other biochemical, morphological and clinical-chemical sign of liver cell injury. This is substantiated by previous results obtained with liver slices and livers in situ (9)(10)(11) and demonstrated here for hepatocytes from livers exposed for 24 h to £>-galactosamine or thioacetamide. Heparan sulphate synthesis was not inhibited in hepatocytes from livers exposed to either of these drug, if the rats were also subject to acute inflammation.…”

“…In accordance with a previously established hypothesis, we propose for liver heparan sulphate a significant role in the pathogenetic sequence of liver cell injury (8). The assumption is based on the experimental observation that the synthesis of both total and liver cell surface heparan sulphate is inhibited almost instantaneously after induction of toxic liver injury by Z>-galactosamine (9) or thioacetamide (10,11). Because of the extraordinarily high Ca 2+ -binding capacity of N-sulphated (heparin-like) glycosaminoglycans (12) this type of proteoglycan is most likely responsible for the high concentration of Ca 2 + at the external cell coat (13).…”

Hyaluronic acid and chondroitin-4-sulphate treatment reduces damage in carbon tetrachloride-induced acute rat liver injury

“…In animals, the total amounts of GAGs in plasma (Ferlazzo et al, 1997) is similar to those measured in humans (Calatroni et al, 1992). Nevertheless, a marked increase in plasma GAG levels was observed in a wide number of diseases (Friman et al, 1987;Laurent et al, 1996;Radhakrishnamurthy et al, 1998;Roughley, 2001) including liver failure in humans (Gressner, 1994;Sanchez-Rodriguez et al, 2000;Plevris et al, 2000) and experimental models such as rats (Gressner and Koster-Eiserfunke, 1981). Since the liver is the main catabolic site for circulating GAGs it became evident that the increased plasma GAG levels are due to the liver failure (Murata et al, 1984).…”

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

“…The commercial sources and specifications of the following materials and reagents have been described previously (4,28): £>-galactosamine hydrochloride, thioacetamide, phosphatebuffered saline, Dulbeccos modifieation of Eagles medium, Measurement ofthe incorporation of( 35 (6) Brought to you by | University of Arizona Authenticated Download Date | 6/7/15 3:37 PM t he Lowry proceduie, using bovine serum albumin s a Standard (30). In vivo labeled, defatted and dried tissue was weighed prior to Suspension in buffered papain.…”