Degradation of mucopolysaccharides by hepatic lysosomes

“…a-N-Acetylglucosaminidase was assayed by the method of O'Brien (14). Lysosomal hyaluronidase activity was measured by a modification of the method of Hutterer (15). The activities of all the other enzymes were measured under the conditions described by Hall et al (16) for fibroblasts, with a few modifications.…”

Section: Abstracgmentioning

confidence: 99%

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Constantopoulos¹,

Rees²,

Cragg³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACGIntracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration of suramin, 500 mg/kg, to 2-month-old rats causes a 5-to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excretion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 Ag of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside Gm2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, f-glucuronidase, and hyaluronidase in the liver of the suramintreated mature rats were consistently decreased, whereas those of a-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 pM or hi er. The activity of -glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncom titive.-The suramin-treated rat may be a useful experimentaFanimal model of mucopolysaccharidosis.Mucopolysaccharidoses (MPS) are diseases caused by the heritable deficiency of lysosomal enzymes necessary for the degradation of glycosaminoglycans (GAG) (1, 2). The genetic defect results in tissue storage and excessive urinary excretion of various partially degraded GAG. In addition, most of these disorders are characterized by sphingolipid abnormalities, particularly of the brain (3). Recently, one of us found that intracerebral injection of the trypanocidal drug suramin resulted in the formation of membranous neuronal and neuroglial inclusions (4). It was suggested that these inclusion bodies may consist of glycolipids and GAG and that the experiment indicated a possible experimental model for storage diseases. The present study was conducted to examine biochemical alterations in the liver and in the brain of rats after intravenous and intracerebral injection of suramin. The pathologic changes found are similar to those detected in the genetic MPS (5) and suggest that the administration of suramin to rats may provide a useful model for the study of the pathogenesis of these diseases. A preliminary report of this work has been published(6). Table 1. Three groups of confrol rats received 0.5 ml of saline. Multiple intracerebral injections of suramin, totaling 40-250 ,ug in 10 ,l of saline (i.e., 4-25 ,ug/,ul) were given to 10-day-old and to 2-month-old rats. Control rats were given 10 ,l of saline. The rats were sacrificed between 7 and 10 days after injection. The livers were removed, weighed, and frozen in liquid nitrogen. Rats receiving intracerebral injections were sacrificed after 2-5 days. The regions of brain about 4 mm in diameter surr...

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“…Livers were obtained at autopsy from 10 nonalcoholic patients who had no liver disease and from 22 alcoholic patients with 3 types of liver injury: 5 had fatty liver, 7 had alcoholic hepatitis and 10 had cirrhosis. Patients with fatty liver died from causes unrelated to liver disease: three with trauma, one with pneumonia, and one with alcoholic delirium.…”

Section: Methodsmentioning

confidence: 99%

“…It has been shown that the hepatic lysosomes contain a hydrolytic enzyme that has substrate specificity similar to testicular hyaluronidase (7). It was suggested that the increase of GAG in cirrhotic livers is due to the accumulation of hepatic hyaluronidase-resistant GAG such as dermatan-SO, (37).…”

Section: Nonextractable Gagmentioning

confidence: 99%

“…An intimate relationship between glycosaminoglycuronans (GAG)' of the ground substance and fiber formation has been described (5,6). The induced fibroblast may produce excessive amounts of GAG, which may or may not be hydrolyzed by lysosomal hyaluronidase (5,7). The present study was undertaken to determine the collagen and GAG concentrations and compositions in normal, fatty, alcoholic hepatitis, and cirrhotic livers.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Natural History of Alcoholic Hepatitis. IV. GLYCOSAMINOGLYCURONANS AND COLLAGEN IN THE HEPATIC CONNECTIVE TISSUE

Galambos¹,

Shapira²

1973

J. Clin. Invest.

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Degradation of mucopolysaccharides by hepatic lysosomes

Cited by 80 publications

References 16 publications

The Rate of Synthesis of Glycosaminoglycans and Collagen by Fibroblasts Cultured from Adult Human Liver Biopsies

The Rate of Synthesis of Glycosaminoglycans and Collagen by Fibroblasts Cultured from Adult Human Liver Biopsies

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Natural History of Alcoholic Hepatitis. IV. GLYCOSAMINOGLYCURONANS AND COLLAGEN IN THE HEPATIC CONNECTIVE TISSUE

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