title: Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver.
abstract: Dopaminergic systems regulate the release of several hormones including growth hormone (GH), thyroid hormones, insulin, glucocorticoids and prolactin (PRL) that play significant roles in the regulation of various Cytochrome P450 (CYP) enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR) and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90) and AhR nuclear translocator (ARNT) was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Harkitis
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: E P
authors.initials: EP
authors.lastname: Daskalopoulos
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: F
authors.initials: F
authors.lastname: Malliou
authors.affiliation: University of Queensland, National Research Centre for Environmental Toxicology (Entox), 39 Kessels Road, Coopers Plains, QLD 4108, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Lang
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Marselos
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Fotopoulos
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Albucharali
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina GR-451 10, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Konstandi
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000737:chemistry; D002273:Carcinogens / Q000737:chemistry; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism; D004298:Dopamine / Q000235:genetics; D065127:Dopamine D2 Receptor Antagonists / Q000737:chemistry*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000378:metabolism
chemical_list: D002273:Carcinogens; D003580:Cytochromes; D065127:Dopamine D2 Receptor Antagonists; D005938:Glucocorticoids; D007328:Insulin; D018336:Receptors, Aryl Hydrocarbon; D017448:Receptors, Dopamine D2; D013963:Thyroid Hormones; D001564:Benzo(a)pyrene; D011388:Prolactin; D003577:Cytochrome P-450 Enzyme System; C076307:methoxyresorufin-O-demethylase; C017170:Cyp1a2 protein, rat; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D004298:Dopamine