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 E(2) (PGE(2)), 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 PGE(2) type 2 receptor (EP(2))-which is coupled to Gs-protein when bound by PGE(2), leading to cAMP production-is involved in this down-regulation. We also determined the possible roles of EP(2) downstream pathways in this down-regulation. We used a primary rat hepatocyte culture model in which EP(2) was shown to be present to study this question. The intracellular cAMP concentration in primary rat hepatocytes was significantly higher after treatment with 1microM PGE(2) than after treatment with 0, 0.01, or 0.1microM PGE(2). Butaprost, an EP(2) agonist, down-regulated CYP 2B1 expression in a dose-dependent manner. SQ22536, an adenylate cyclase inhibitor, reversed the down-regulation by PGE(2) as did H-89, a protein kinase A inhibitor. These results suggest that EP(2) and the downstream pathways of cAMP and protein kinase A are involved in the down-regulation of CYP 2B1 expression by PGE(2) in the presence of phenobarbital.
Li
Chien-Chun
CC
Department of Nutritional Science, Chung Shan Medical University, Taichung, Taiwan.
Shen
Hui-Lan
HL
Lii
Chong-Kuei
CK
Liu
Kai-Li
KL
Yang
Jaw-Ji
JJ
Chen
Haw-Wen
HW
D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D010634:Phenobarbital / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype
D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D019362:Cytochrome P-450 CYP2B1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; D010634:Phenobarbital