It is well known that phenobarbital (PB) treatment produces an increase in the amount of cytoplasmic membranes of hepatocytes, with a parallel enhancement in the activity of drug-metabolizing enzymes. However, little is known about how the induced membranes are removed after the drug treatment is stopped. To consider this problem, the recovery of rat hepatocytes from PB induction (five daily injections, 100 mg/kg) was followed morphometrically. Treatment with PB produced a cellular enlargement (26%) due to increases in the volume of the cytoplasmic matrix (20%) and the volume (100%) and surface area (90%) of the smooth-surfaced endoplasmic reticulum (SER). The volume of the nuclei and the surface area of the Golgi apparatus were also increased, but no changes were detected in the volumes of the mitochondria or peroxisomes. The SER membranes induced by the PB were removed within 5 days after the end of the treatment period. During this period of membrane removal, we observed an increase in the volume (800%) and number (96%) of autophagic vacuoles without a change in dense bodies. A morphometric analysis of the content of the autophagic vacuoles showed that the endoplasmic reticulum membranes were preferentially removed, and from this we conclude that the formation of autophagic vacuoles was not a random process. Our findings show that the removal of excess cytoplasmic membranes is associated with an increase in autophagic activity and thus demonstrates the presence of a specific cellular mechanism which may be responsible for the bulk removal of PB-induced membranes.

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