Drug-induced lysosomal storage of sulphated glycosaminoglycans.
1. Certain compounds (e.g., the immunomodulator tilorone and congeners) are able to induce lysosomal storage of sulphated glycosaminoglycans (GAG), thus, producing cytological and biochemical alterations reminiscent of the inherited mucopolysaccharidoses. The drug-induced GAG storage has been studied in cultured fibroblasts of several species and in rats, and it is likely to occur also in humans. 2. The cytological hallmarks of GAG storage are enlarged lysosomes congested with material that is intensely stained by cationic dyes. With respect to fixation techniques, one has to keep in mind that the GAGs are highly water-soluble and are leached during conventional fixation and tissue processing. Biochemically, the elevation of GAG contents in tissues and cultured fibroblasts is due to storage of dermatan sulphate, predominantly. 3. The molecular structure of the potent inducers of GAG storage is characterized by a planar tricyclic aromatic ring system that is symmetrically substituted with two side chains of 4-5 sigma bond length, each carrying a protonizable nitrogen atom. The lysosomal storage of GAG is accompanied by lysosomal accumulation of the inducing drug, with the molar ratio of drug to GAG-disaccharide unit amounting to > 1:1. The reversibility of GAG storage is rather slow. 4. The pathogenic mechanisms underlying the drug side effects are discussed and the following hypothesis is put forward: The compounds in question are lysosomotropic weak bases. They get trapped in the acidic lysosomes and accumulate highly there. Physicochemical data suggest that the drugs form complexes with the sulphated GAGs, particularly with dermatan sulphate: The positively charged nitrogen atoms of the drug side chains interact with the negative charges of sulphate and carboxy groups of the GAGs, thereby crosslinking at least two GAG helices. Moreover, the interlinking drug molecules form parallel stacks resulting from interaction of the aromatic pi-electrons of the planar ring systems. This further stabilizes the complexes. The GAGs within the complexes are thought to be resistant to the degrading lysosomal enzymes. 5. Drug-induced GAG storage has not been directly demonstrated in man. Yet, clinical reports on keratopathy and basophilic cytoplasmic inclusions in blood lymphocytes of tilorone-treated patients suggest that this drug side effect may also occur in man.
Fischer
J
J
Department of Pharmacology, University of Kiel, Germany.
Lüllmann
H
H
Lüllmann-Rauch
R
R
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D002417:Cattle; D003871:Dermatan Sulfate / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016464:Lysosomal Storage Diseases / Q000139:chemically induced* / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013994:Tilorone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry; D014018:Tissue Distribution
D000276:Adjuvants, Immunologic; D006025:Glycosaminoglycans; D003871:Dermatan Sulfate; D013994:Tilorone