Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver
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-r...
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| creator | Harkitis, P Daskalopoulos, E P Malliou, F Lang, M A Marselos, M Fotopoulos, A Albucharali, G Konstandi, M |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0128708 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0128708</identifier><identifier>PMID: 26466350</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Animals ; Aromatic compounds ; Benzo(a)pyrene ; Benzo(a)pyrene - chemistry ; Carcinogenicity ; Carcinogens ; Carcinogens - chemistry ; Control ; CYP1A2 protein ; Cytochrome ; Cytochrome P-450 CYP1A1 - metabolism ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP1B1 - metabolism ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome P450 ; Cytochromes - metabolism ; Deactivation ; Dopamine ; Dopamine - genetics ; Dopamine D2 Receptor Antagonists - chemistry ; Dopamine D2 receptors ; Down-Regulation ; Drugs ; Environmental risk ; Enzymes ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Genes ; Glucocorticoids ; Glucocorticoids - metabolism ; Growth hormone ; Growth hormones ; Heat shock proteins ; Hepatocytes - metabolism ; Hormones ; Hsp90 protein ; Hydrocarbons ; Inactivation ; Insulin ; Insulin - metabolism ; Kinases ; Laboratory animals ; Liver ; Liver - drug effects ; Liver - metabolism ; Male ; Medical research ; Metabolism ; Metabolites ; Microsomes, Liver - metabolism ; Nuclear medicine ; Pathways ; Pharmacology ; Pollutants ; Prolactin ; Prolactin - metabolism ; Proteins ; Pyrene ; Rats ; Rats, Wistar ; Receptors ; Receptors, Aryl Hydrocarbon - metabolism ; Receptors, Dopamine D2 - metabolism ; Risk reduction ; Rodents ; Signal Transduction ; Studies ; Sulpiride ; Thyroid ; Thyroid hormones ; Thyroid Hormones - metabolism ; Toxicants ; Toxicity ; Toxicology ; Transduction</subject><ispartof>PloS one, 2015-10, Vol.10 (10), p.e0128708-e0128708</ispartof><rights>2015 Harkitis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Harkitis et al 2015 Harkitis et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4418-f19e51ec633f08ee757c4ff06e2b2ac167caba9c555f276303305a63ced3f84a3</citedby><cites>FETCH-LOGICAL-c4418-f19e51ec633f08ee757c4ff06e2b2ac167caba9c555f276303305a63ced3f84a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605514/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605514/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26466350$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Makishima, Makoto</contributor><creatorcontrib>Harkitis, P</creatorcontrib><creatorcontrib>Daskalopoulos, E P</creatorcontrib><creatorcontrib>Malliou, F</creatorcontrib><creatorcontrib>Lang, M A</creatorcontrib><creatorcontrib>Marselos, M</creatorcontrib><creatorcontrib>Fotopoulos, A</creatorcontrib><creatorcontrib>Albucharali, G</creatorcontrib><creatorcontrib>Konstandi, M</creatorcontrib><title>Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Aromatic compounds</subject><subject>Benzo(a)pyrene</subject><subject>Benzo(a)pyrene - chemistry</subject><subject>Carcinogenicity</subject><subject>Carcinogens</subject><subject>Carcinogens - chemistry</subject><subject>Control</subject><subject>CYP1A2 protein</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP1A1 - metabolism</subject><subject>Cytochrome P-450 CYP1A2</subject><subject>Cytochrome P-450 CYP1B1 - metabolism</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome P450</subject><subject>Cytochromes - metabolism</subject><subject>Deactivation</subject><subject>Dopamine</subject><subject>Dopamine - genetics</subject><subject>Dopamine D2 Receptor Antagonists - chemistry</subject><subject>Dopamine D2 receptors</subject><subject>Down-Regulation</subject><subject>Drugs</subject><subject>Environmental risk</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Genes</subject><subject>Glucocorticoids</subject><subject>Glucocorticoids - metabolism</subject><subject>Growth hormone</subject><subject>Growth hormones</subject><subject>Heat shock proteins</subject><subject>Hepatocytes - metabolism</subject><subject>Hormones</subject><subject>Hsp90 protein</subject><subject>Hydrocarbons</subject><subject>Inactivation</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Medical research</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Microsomes, Liver - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Harkitis, P</au><au>Daskalopoulos, E P</au><au>Malliou, F</au><au>Lang, M A</au><au>Marselos, M</au><au>Fotopoulos, A</au><au>Albucharali, G</au><au>Konstandi, M</au><au>Makishima, Makoto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-10-14</date><risdate>2015</risdate><volume>10</volume><issue>10</issue><spage>e0128708</spage><epage>e0128708</epage><pages>e0128708-e0128708</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26466350</pmid><doi>10.1371/journal.pone.0128708</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-10, Vol.10 (10), p.e0128708-e0128708 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1722187596 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Animals Aromatic compounds Benzo(a)pyrene Benzo(a)pyrene - chemistry Carcinogenicity Carcinogens Carcinogens - chemistry Control CYP1A2 protein Cytochrome Cytochrome P-450 CYP1A1 - metabolism Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP1B1 - metabolism Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Cytochromes - metabolism Deactivation Dopamine Dopamine - genetics Dopamine D2 Receptor Antagonists - chemistry Dopamine D2 receptors Down-Regulation Drugs Environmental risk Enzymes Gene expression Gene Expression Profiling Gene Expression Regulation, Enzymologic Genes Glucocorticoids Glucocorticoids - metabolism Growth hormone Growth hormones Heat shock proteins Hepatocytes - metabolism Hormones Hsp90 protein Hydrocarbons Inactivation Insulin Insulin - metabolism Kinases Laboratory animals Liver Liver - drug effects Liver - metabolism Male Medical research Metabolism Metabolites Microsomes, Liver - metabolism Nuclear medicine Pathways Pharmacology Pollutants Prolactin Prolactin - metabolism Proteins Pyrene Rats Rats, Wistar Receptors Receptors, Aryl Hydrocarbon - metabolism Receptors, Dopamine D2 - metabolism Risk reduction Rodents Signal Transduction Studies Sulpiride Thyroid Thyroid hormones Thyroid Hormones - metabolism Toxicants Toxicity Toxicology Transduction |
| title | Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver |
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