title: D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1.
abstract: This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by l-DOPA. Stimulation of D(2)-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D(2)-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D(2)-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D(1)-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(alpha)pyrene (B(alpha)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(alpha)P modified the impact of central and peripheral catecholamines and alpha(2)-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(alpha)P, alpha(2)-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha(2)-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies.
authors.affiliation: Department of Pharmacology, Medical School, University of Ioannina, Ioannina GR-451 10, Greece. mkonstan@cc.uoi.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Konstandi
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Harkitis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kostakis
authors.forename: Marios
authors.initials: M
authors.lastname: Marselos
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Johnson
authors.forename: Matti A
authors.initials: MA
authors.lastname: Lang
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D015153:Blotting, Western; D002395:Catecholamines / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D065127:Dopamine D2 Receptor Antagonists; D015536:Down-Regulation; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D002395:Catecholamines; D065127:Dopamine D2 Receptor Antagonists; D007527:Isoenzymes; D017448:Receptors, Dopamine D2; D001564:Benzo(a)pyrene; D019392:Cytochrome P-450 CYP2E1