Abstract
Phenobarbital sodium (PB) was administered intramuscularly once a day to beagle dogs aged 10 to 13 months old, and measurement of hepatic drug-metabolizing enzyme (aminopyrine-N-demethylase and aniline hydroxylase) activites, histopathology, and electron microscopy were carried out on liver samples collected after 4 and 14 days treatment. After 4 days treatment, marked increases in hepatic drug-metabolizing enzyme activities were noted. Morphologically, hypertrophy of hepatocytes, accompanied by a ground glass-appearance, was observed on light microscopy, and proliferation of smooth endoplasmic reticulum (sER) and rough endoplasmic reticulum (rER), with wave- or horseshoe-shaped arrangements of the proliferated rER, were observed by electron microscopy. After 14 days, hepatic drug-metabolizing enzyme activities were increased compared with those after 4 days treatment, and eosinophilic intracytoplasmic inclusion bodies were observed in the hepatocytes. The inclusion bodies showed a positive reaction for sudan black B staining, indicating the presence of phospholipids. On electron microscopy, these inclusion bodies corresponded to myelin figures (MFs), and continuity of the membranes between MF and proliferated sER or rER was noted. When the animals were treated with cobalt chloride which is an inhibitor of P-450 synthesis, increases in hepatic drug-metabolizing enzyme activities induced by PB were suppressed; however, proliferation of sER and rER was not inhibited and horseshoe-arranged rER, a precursor of the inclusion bodies, was still observed. From these results, it was considered that the inclusion bodies in the dog hepatocytes induced by PB were related to sER proliferation.
