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 cr-glucosidase-l inhibitor, is a candidate anti-HIV agent targeted aga inst viral glycoprotein processing in host cell endoplasmic reticulum. The potential toxicity of this compound was evaluated in Sprague-Dawl ey 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 p ancreas. 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, whi ch sometimes contained homogeneously stained, moderately electron-dens e material. The vacuoles in thyroid follicular cells contained pale eo sinophilic colloidlike material consistent with accumulated thyroglobu lin, 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 ana lyses. The morphologic changes were completely reversed after a 4-wk r ecovery period. The incidence and severity of histologic changes were decreased after 13 and 26 wk of treatment compared to 4 wk of treatmen t, indicating an attenuation of the host response or adaptation to the prolonged p-N-butyl-DNJ administration. We believe that morphologic c hanges in thyroid follicular cells, salivary gland acinar cells, pancr eatic acinar cells, and gastric chief cells were the result of nonspec ific inhibition of host alpha-glucosidase(s) by p-N-butyl-DNJ, causing clinically silent perturbation in host cell glycoprotein processing a nd/or glycoprotein transport.