The distribution of cytochrome P-450-mediated drug oxidation and glutathione in periportal and perivenous rat hepatocytes after phenobarbital treatment.

The effect of phenobarbital pretreatment on acinar distribution of microsomal drug metabolizing enzymes was investigated by analysis of periportal (pp) and perivenous (pv) enriched rat hepatocytes isolated by collagenase gradient perfusion. In untreated animals the activities of cytochrome P-450, NADPH-cytochrome c reductase and microsomal ethanol oxidation were significantly higher in pv cells. Phenobarbital produced a 45% increase of the yielded microsomes related to the hepatocytic protein but did not change their relative distribution. The content of reduced glutathione (GSH) was lower in hepatocytes from the pv area. The GSH content was more than 20% increased after phenobarbital treatment in both subclasses of cells, but the distribution pattern remained unchanged. The higher activity of drug metabolizing enzymes in the pv area of untreated animals may account for the higher cytotoxicity of numerous drugs to the perivenous hepatocytes. A 3-day treatment with phenobarbital equalized the pp-pv difference by producing more induction of the periportal cytochrome P-450-mediated drug and ethanol oxidation capacities in microsomes derived from periportally enriched hepatocytes.