The tilorone-induced mucopolysaccharidosis in rats. Biochemical investigations.
The tissues of rats chronically treated with tilorone exhibited a significant accumulation of acid glycosaminoglycans (GAGs): In the liver, the GAG concentration was found to be elevated by a factor of 38, in the spleen by a factor 15 and in the kidneys by a factor of 5. Furthermore, the renal excretion of GAGs was increased 32-fold as compared to control animals. Dermatan sulphate was predominant among the GAGs stored in the three organs; chondroitin sulphate and heparan sulphate were found in smaller amounts. GAG storage was accompanied by accumulation of the drug within the tissues: the molar ratio of tilorone per disaccharide unit of GAG was calculated to be one to two in each tissue. According to previous reports, tilorone-induced mucopolysacchariodosis is due to impaired lysosomal degradation of GAGs. The present results give support to the hypothesis that an interaction between the polyanionic GAGs and the dicationic drug may lead to GAG-drug complexes which cannot be digested by lysosomal enzymes.
Prokopek
M
M
Department of Pharmacology, University of Kiel, Federal Republic of Germany.
D000818:Animals; D002810:Chondroitinases and Chondroitin Lyases / Q000494:pharmacology; D003401:Creatine / Q000652:urine; D004586:Electrophoresis; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism / Q000652:urine; D006603:Hexuronic Acids / Q000378:metabolism / Q000652:urine; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects; D009083:Mucopolysaccharidoses / Q000139:chemically induced* / Q000473:pathology; D009608:Nitrous Acid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000737:chemistry / Q000378:metabolism; D013194:Staining and Labeling; D013994:Tilorone / Q000009:adverse effects* / Q000378:metabolism
D006025:Glycosaminoglycans; D006603:Hexuronic Acids; D002810:Chondroitinases and Chondroitin Lyases; D003401:Creatine; D013994:Tilorone; D009608:Nitrous Acid