Drug-induced intralysosomal storage of sulfated glycosaminoglycans (GAGs): a methodical pitfall occurring with acridine derivatives.
The present communication deals with an adverse drug action which is exerted by a series of dicationic amphiphilic compounds such as the immunomodulatory drug tilorone and congeners. The drugs induce lysosomal storage of sulfated glycosaminoglycans (GAGs) in intact organisms and in cultured cells by impairing the lysosomal GAG degradation. This impairment was proposed to be due to the formation of non-degradable GAG-drug complexes. GAGs are highly water-soluble and not preservable by aldehyde fixatives. Therefore, usually the lysosomes appear optically empty in histological preparations, unless the fixative is supplemented with a GAG-precipitating agent. When acridine derivatives were used for the induction of GAG-storage, the lysosomal storage material displayed unexpected and unsystematic variability with regard to its preservability and ultrastructure. In the present study, evidence is presented that the acridine derivatives (a) remain bound to the stored GAGs for some time after glutaraldehyde fixation; and (b) they precipitate GAGs in vitro. Thus, apart from their unwanted action in the living cell, i.e., disturbing lysosomal GAG-degradation, the drugs function as precipitants and "fixatives" for the intralysosomal GAGs. The uncontrolled persistence of the drugs after tissue fixation leads to variable degree of GAG-preservation and thus to unpredictable variability of the ultrastructure of the storage lysosomes. If this pitfall is not realized, the resulting inconsistencies may rise confusion among toxicologic pathologists who deal with drug-induced lysosomal storage disorders.
Lüllmann-Rauch
R
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Department of Anatomy, University of Kiel, Germany.
D000166:Acridines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006025:Glycosaminoglycans / Q000032:analysis / Q000378:metabolism*; D006651:Histocytochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016464:Lysosomal Storage Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D051381:Rats; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013994:Tilorone / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D016707:Tissue Fixation / Q000379:methods
D000166:Acridines; D000276:Adjuvants, Immunologic; D006025:Glycosaminoglycans; C075219:3,6-bis(2-(diethylamino)ethoxy)acridine; C045570:3,6-bis(2-piperidinoethoxy)acridine trihydrochloride; D013994:Tilorone