Prostaglandin E2 down-regulation of cytochrome P-450 2B1 expression induced by phenobarbital is through EP2 receptor in rat hepatocytes

Cytochrome P-450 is an important bioactivation-detoxification system in vivo. Its expression is regulated by foreign chemicals and dietary factors, and lipids have been found to regulate its gene expression. We showed previously that prostaglandin E2 (PGE2), a fatty acid metabolite, down-regulates cytochrome P-450 2B1 (CYP 2B1) expression induced by phenobarbital. The objective of the present study was to determine whether PGE2 type 2 receptor (EP2)-which is coupled to Gs-protein when bound by PGE2, leading to cAMP production-is involved in this down-regulation. We also determined the possible roles of EP2 downstream pathways in this down-regulation. We used a primary rat hepatocyte culture model in which EP2 was shown to be present to study this question. The intracellular cAMP concentration in primary rat hepatocytes was significantly higher after treatment with 1 μM PGE2 than after treatment with 0, 0.01, or 0.1 μM PGE2. Butaprost, an EP2 agonist, down-regulated CYP 2B1 expression in a dose-dependent manner. SQ22536, an adenylate cyclase inhibitor, reversed the down-regulation by PGE2 as did H-89, a protein kinase A inhibitor. These results suggest that EP2 and the downstream pathways of cAMP and protein kinase A are involved in the down-regulation of CYP 2B1 expression by PGE2 in the presence of phenobarbital.