title: n-6 and n-3 polyunsaturated fatty acids down-regulate cytochrome P-450 2B1 gene expression induced by phenobarbital in primary rat hepatocytes.
abstract: In mammals, polyunsaturated fatty acids (PUFAs) act not only as an important energy source, but also as substrates for cellular membrane and hormone formation. They also play key roles in cellular metabolism and gene regulation. The objective of the present study was to determine whether individual n-6 and n-3 PUFAs affect cytochrome P-450 2B1 (CYP 2B1) expression induced by phenobarbital (PB) in primary rat hepatocytes. We used 100-microM arachidonic acid (AA), linoleic acid, eicosapentaenoic acid and docosahexaenoic acid (DHA) to test this hypothesis. Phenobarbital-induced CYP 2B1 expression was down-regulated by n-6 and n-3 PUFAs, especially AA and DHA. Prostaglandin (PG) E2 but not PGE3 was found to down-regulate PB-induced CYP 2B1 expression. The cyclooxygenase inhibitor indomethacin (20 microM) attenuated the down-regulation of CYP 2B1 gene expression by n-6 and n-3 PUFAs induced by PB, and maximal attenuation was found in the AA-treated group. We also studied the PGE2 downstream cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway to determine its role in the down-regulation of CYP 2B1 expression by AA with the use of 0.4 mM of the adenylate cyclase inhibitor 9-(tetrahydro-2'-furyl)adenine] (SQ22536) and 7.5 microM of the PKA inhibitor H-89. Both inhibitors attenuated the down-regulation of CYP 2B1 expression by AA. These results suggest that PB-induced CYP 2B1 expression is down-regulated by n-6 and n-3 PUFAs through different pathways. Prostaglandin E2 and the cAMP-dependent PKA pathway were involved in AA down-regulation of CYP 2B1 expression, whereas the down-regulation by n-3 PUFAs is not fully understood yet and the glucocorticoid receptor/constitutive androstane receptor/retinoid X receptor signal transduction cascade can be involved.
authors.affiliation: Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan.
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Jaw-Ji
authors.initials: JJ
authors.lastname: Yang
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology*; D007213:Indomethacin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C033246:prostaglandin E3; D007770:L-Lactate Dehydrogenase; D019362:Cytochrome P-450 CYP2B1; D017868:Cyclic AMP-Dependent Protein Kinases; D000527:Alprostadil; D015232:Dinoprostone; D007213:Indomethacin; D010634:Phenobarbital