Dopamine D2-receptor antagonists down-regulate CYP1A1/2 and CYP1B1 in the rat liver

Harkitis, P., Daskalopoulos, E. P., Malliou, F., Lang, M. A., Marselos, M., Fotopoulos, A., Albucharali, G. and Konstandi, M. (2015) Dopamine D2-receptor antagonists down-regulate CYP1A1/2 and CYP1B1 in the rat liver. PLoS One, 10 10: 1-21. doi:10.1371/journal.pone.0128708

Author Harkitis, P.
Daskalopoulos, E. P.
Malliou, F.
Lang, M. A.
Marselos, M.
Fotopoulos, A.
Albucharali, G.
Konstandi, M.
Title Dopamine D2-receptor antagonists down-regulate CYP1A1/2 and CYP1B1 in the rat liver
Formatted title
Dopamine D2-receptor antagonists down-regulate CYP1A1/2 and CYP1B1 in the rat liver
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2015-10-14
Year available 2015
Sub-type Article (original research)
DOI 10.1371/journal.pone.0128708
Open Access Status DOI
Volume 10
Issue 10
Start page 1
End page 21
Total pages 21
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
National Research Centre for Environmental Toxicology Publications
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