Prostaglandin E2 is involved in the increase of cytochrome P-450 2B1 expression by α-tocopheryl succinate in primary rat hepatocytes in the presence of phenobarbital

The modulation of cytochrome P-450 2B1 expression by α-tocopheryl succinate and whether prostaglandin E2 is involved in this modulation in primary rat hepatocytes in the presence of phenobarbital were investigated. A primary rat hepatocyte culture model that faithfully reproduces the phenobarbital response observed in vivo was used. Intracellular α-tocopherol content was dose dependently increased by α-tocopheryl succinate incubation. Hepatocytes were demonstrated to have prostaglandin E2-synthesizing capability. α-Tocopheryl succinate inhibited prostaglandin E2 synthesis by hepatocytes and increased cytochrome P-450 2B1 expression in the presence of phenobarbital; however, it had little effect on intracellular cAMP level. To mimic the exogenous source of prostaglandin E2 from non-parenchymal cells, various concentrations of prostaglandin E2 were added to the cell culture. High doses of exogenous prostaglandin E2 (100 and 1,000 nM) inhibited the cytochrome P-450 2B1 expression in the presence of phenobarbital compared with low doses (1 and 10 nM); however, the presence of high doses of prostaglandin E2 had no effect on intracellular cAMP level. Forskolin significantly increased intracellular cAMP level and inhibited cytochrome P-450 2B1 expression in the presence of phenobarbital. The results of this study indicate that α-tocopheryl succinate increases cytochrome P-450 2B1 expression via its inhibition of prostaglandin E2 synthesis in the presence of phenobarbital; however, changes in intracellular cAMP level are not related to cytochrome P-450 2BI expression.