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

Abstract

The modulation of cytochrome P-450 2B1 expression by alpha-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 alpha-tocopherol content was dose dependently increased by alpha-tocopheryl succinate incubation. Hepatocytes were demonstrated to have prostaglandin E2-synthesizing capability. alpha-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 nonparenchymal 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 alpha-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 2B1 expression.

n-6 and n-3 Polyunsaturated fatty acids down-regulate cytochrome P-450 2B1 gene expression induced by phenobarbital in primary rat hepatocytes☆

“…Cyclooxygenase, which is also known as PG synthase, is the key enzyme for PG synthesis. Prostaglandin E 2 , one of the end products of the COX metabolic pathway, can downregulate PB-induced CYP 2B1 expression in primary rat hepatocytes [36], and this down-regulation is through the EP 2 receptor [23]. In the present study, PGE 2 levels were significantly greater in the AA-treated group than in the other groups (Fig.…”

The combined effects of garlic oil and fish oil on the hepatic antioxidant and drug-metabolizing enzymes of rats

“…Moreover, a-tocopherol modulation on the drug-metabolizing enzyme activity and expression is an alternative explanation. Recently, we demonstrated that a-tocopherol up-regulates CYP2B1 expression via prostaglandin E 2 -mediated pathways (Tsai et al 2001). Such an effect may explain in part the higher CYP protein and mRNA content in the high-FO group, which had a greater a-tocopherol level than the MO-fed groups.…”

Docosahexaenoic acid down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes via the sphingomyelinase/ceramide pathway

“…The oxazaphosphorine anticancer prodrug CPA is mainly activated by a liver P450 2B-catalyzed 4-hydroxylation that yields active and cytotoxic metabolites [24]. Dietary nutrients such as vitamin E and DHA have been shown to influence PB-induced CYP 2B1 gene expression in rat primary hepatocytes [21,25]. The underlying mechanisms of this influence are changes in prostaglandin E 2 (PGE 2 ) production and alteration of transcription factor translocation, respectively.…”