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Lysosomal-Storage Disorder Induced by Elmiron Following 90-Days Gavage Administration in Rats and MiceLaboratory of Experimental Pathology National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709, nyska{at}niehs.nih.gov
Pathology Associates-A Charles River Company, 4915 D Prospectus Drive, Durham, North Carolina 27713
Battelle Columbus Laboratories, 505 King Avenue, Columbus, Ohio 43201
Environmental Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709 Elmiron, a highly sulfated, semisynthetic pentose polysaccharide with properties similar to heparin, is used for the treatment of interstitial cystitis. Thirteen-week gavage studies were conducted by administering the drug in deionized water to F344/N rats and B6C3F1 mice once daily, 5 days per week for up to 13 consecutive weeks, at doses of 0, 63, 125, 250, 500, and 1,000 mg/kg body weight. No significant drug-related effects were observed in body weight, survival, clinical, and necropsy results. Significant organ weight increases were seen in the liver, lungs, and spleen of both species and the kidneys of rats, mainly in groups treated with 250 mg/kg/day and above. Hematological analysis indicated increases for both species in the white blood cell and lymphocyte counts. Sites of toxicity identified histopathologically were the rectum, liver, mesenteric and mandibular lymph nodes (both sexes), spleen (mice only), and lungs and kidneys (rats only). Lesions consisted mainly of infiltration into multiple tissues of vacuolated histiocytes, which, by histochemical investigation, indicated the presence of neutral and acidic mucins and lipidic material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. On the basis of our findings, we propose that Elmiron was absorbed through the focally disrupted rectal mucosa, was deposited in the lamina propria, accumulated within macrophages, and then was distributed by these cells or as a free chemical via the lymphatics and blood, to the various organ sites manifesting histiocytic infi ltration. The cytoplasmic membrane-bound structures within macrophages were lysosomes containing membranous material of cellular origin and, perhaps, remnants of the deposited test material, Elmiron.
Key Words: Sodium pentosan polysulfate • polysaccharide • rodents • rectum • macrophage.
Toxicologic Pathology, Vol. 30, No. 2,
178-187 (2002) This article has been cited by other articles:
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