Pathology of perbutylated-N-butyl-1-deoxynojiromycin (an alpha-glucosidase-1 inhibitor) in Sprague-Dawley rats.
Perbutylated-N-butyl-1-deoxynojiromycin (p-N-butyl-DNJ, SC-49483), an alpha-glucosidase-1 inhibitor, is a candidate anti-HIV agent targeted against viral glycoprotein processing in host cell endoplasmic reticulum. The potential toxicity of this compound was evaluated in Sprague-Dawley rats after 4, 13, or 26 wk of oral administration at doses ranging from 300 to 3,670 mg/kg/day. In these studies, the target organs of p-N-butyl-DNJ effects were thyroid gland, salivary gland, stomach, and pancreas. The most prominent histologic change in these organs was the presence of clear or lightly eosinophilic vacuoles in the cytoplasm of thyroid follicular cells, gastric chief cells, salivary gland acinar cells, and exocrine pancreatic acinar cells. Ultrastructurally, these vacuoles were consistent with dilated rough endoplasmic reticulum, which sometimes contained homogeneously stained, moderately electron-dense material. The vacuoles in thyroid follicular cells contained pale eosinophilic colloidlike material consistent with accumulated thyroglobulin, as shown by immunohistochemical staining methods. The biological functions of these organs were not adversely affected as evidenced by the absence of clinical signs and the results of selected hormonal analyses. The morphologic changes were completely reversed after a 4-wk recovery period. The incidence and severity of histologic changes were decreased after 13 and 26 wk of treatment compared to 4 wk of treatment, indicating an attenuation of the host response or adaptation to the prolonged p-N-butyl-DNJ administration. We believe that morphologic changes in thyroid follicular cells, salivary gland acinar cells, pancreatic acinar cells, and gastric chief cells were the result of nonspecific inhibition of host alpha-glucosidase(s) by p-N-butyl-DNJ, causing clinically silent perturbation in host cell glycoprotein processing and/or glycoprotein transport.
Khan
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Department of Product Safety Assessment, Searle Research & Development, Skokie, Illinois 60077, USA.
Snook
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Semler
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Baron
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Alden
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D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D002087:Butyrates / Q000633:toxicity*; D005260:Female; D065089:Glycoside Hydrolase Inhibitors; D008297:Male; D010179:Pancreas / Q000187:drug effects; D010880:Piperidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012469:Salivary Glands / Q000187:drug effects; D013270:Stomach / Q000187:drug effects; D013961:Thyroid Gland / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D013974:Thyroxine / Q000096:biosynthesis; D014284:Triiodothyronine / Q000096:biosynthesis
D000998:Antiviral Agents; D002087:Butyrates; D065089:Glycoside Hydrolase Inhibitors; D010880:Piperidines; D014284:Triiodothyronine; C096960:glycovir; D013974:Thyroxine