{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:49:05Z","timestamp":1762868945166,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,6]],"date-time":"2022-11-06T00:00:00Z","timestamp":1667692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre","award":["2018\/31\/N\/NZ\/01857"],"award-info":[{"award-number":["2018\/31\/N\/NZ\/01857"]}]},{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences","award":["2018\/31\/N\/NZ\/01857"],"award-info":[{"award-number":["2018\/31\/N\/NZ\/01857"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg\/kg ip.) for two weeks. The activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1\u2032-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of CYP2D1 without affecting that of CYP2D2, CYP2D3, CYP2D4, and CYP2D5. In conclusion, lurasidone regulates brain (but not liver) CYP2D activity\/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors\/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures.<\/jats:p>","DOI":"10.3390\/cells11213513","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T02:43:51Z","timestamp":1667789031000},"page":"3513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Atypical Antipsychotic Lurasidone Affects Brain but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schizophrenia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7137-2990","authenticated-orcid":false,"given":"Przemys\u0142aw J.","family":"Danek","sequence":"first","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1226-1721","authenticated-orcid":false,"given":"W\u0142adys\u0142awa A.","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 Enzymes in Drug Metabolism: Regulation of Gene Expression, Enzyme Activities, and Impact of Genetic Variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115006","DOI":"10.1016\/j.bcp.2022.115006","article-title":"The Mechanisms of Interactions of Psychotropic Drugs with Liver and Brain Cytochrome P450 and Their Significance for Drug Effect and Drug-Drug Interactions","volume":"199","author":"Daniel","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0304-4165(97)00157-8","article-title":"Tissue Distributions of CYP2D1, 2D2, 2D3 and 2D4 MRNA in Rats Detected by RT-PCR","volume":"1380","author":"Hiroi","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1124\/dmd.30.9.970","article-title":"Catalytic Specificity of CYP2D Isoforms in Rat and Human","volume":"30","author":"Hiroi","year":"2002","journal-title":"Drug Metab. Dispos."},{"key":"ref_5","first-page":"1148","article-title":"Cytochromes P450 of the 2D Subfamily in Rat Brain","volume":"47","author":"Wyss","year":"1995","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1517\/17425255.2.6.875","article-title":"Species Differences between Mouse, Rat, Dog, Monkey and Human CYP-Mediated Drug Metabolism, Inhibition and Induction","volume":"2","author":"Martignoni","year":"2006","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"297","DOI":"10.2174\/138920007780655478","article-title":"Expression and Function of Cytochrome P450 in Brain Drug Metabolism","volume":"8","author":"Meyer","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1503\/jpn.120133","article-title":"Cytochrome P450-Mediated Drug Metabolism in the Brain","volume":"38","author":"Miksys","year":"2013","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_9","first-page":"342","article-title":"Cytochrome P4502D4 in the Brain: Specific Neuronal Regulation by Clozapine and Toluene","volume":"50","author":"Hedlund","year":"1996","journal-title":"Mol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s40262-016-0465-5","article-title":"Pharmacokinetics and Pharmacodynamics of Lurasidone Hydrochloride, a Second-Generation Antipsychotic: A Systematic Review of the Published Literature","volume":"56","author":"Greenberg","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1517\/14656566.2012.712114","article-title":"Iloperidone, Asenapine and Lurasidone: A Primer on Their Current Status","volume":"13","author":"Tarazi","year":"2012","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2147\/NDT.S18059","article-title":"Critical Appraisal of Lurasidone in the Management of Schizophrenia","volume":"8","author":"Caccia","year":"2012","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.pharep.2016.04.002","article-title":"Lurasidone: The 2016 Update on the Pharmacology, Efficacy and Safety Profile","volume":"68","author":"Jaeschke","year":"2016","journal-title":"Pharmacol. Rep."},{"key":"ref_14","first-page":"1163","article-title":"Clinical Pharmacology of Atypical Antipsychotics: An Update","volume":"13","author":"Mauri","year":"2014","journal-title":"EXCLI J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105209","DOI":"10.1016\/j.neuint.2021.105209","article-title":"Chronic Treatment with Asenapine Affects Cytochrome P450 2D (CYP2D) in Rat Brain and Liver. Pharmacological Aspects","volume":"151","author":"Danek","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Danek, P.J., and Daniel, W.A. (2021). Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms. Cells, 10.","DOI":"10.3390\/cells10123472"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1007\/s43440-020-00102-5","article-title":"The Atypical Neuroleptics Iloperidone and Lurasidone Inhibit Human Cytochrome P450 Enzymes in Vitro. Evaluation of Potential Metabolic Interactions","volume":"72","author":"Danek","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1038\/npp.2012.64","article-title":"Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT(1A) Partial Agonist","volume":"37","author":"Horiguchi","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1111\/jnc.12512","article-title":"Comparative Effect of Lurasidone and Blonanserin on Cortical Glutamate, Dopamine, and Acetylcholine Efflux: Role of Relative Serotonin (5-HT)2A and DA D2 Antagonism and 5-HT1A Partial Agonism","volume":"128","author":"Huang","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.bbr.2015.10.044","article-title":"Nicotinic Receptors and Lurasidone-Mediated Reversal of Phencyclidine-Induced Deficit in Novel Object Recognition","volume":"301","author":"Miyauchi","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_21","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates, Academic Press. [6th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1210\/endo.142.9.8363","article-title":"Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain","volume":"142","author":"Hiroi","year":"2001","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1211\/002235702162","article-title":"Inhibition and Possible Induction of Rat CYP2D after Short- and Long-Term Treatment with Antidepressants","volume":"54","author":"Daniel","year":"2002","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.bcp.2018.09.005","article-title":"The Activity of Brain and Liver Cytochrome P450 2D (CYP2D) Is Differently Affected by Antidepressants in the Chronic Mild Stress (CMS) Model of Depression in the Rat","volume":"156","author":"Haduch","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1111\/j.1471-4159.2011.07339.x","article-title":"Cytochrome P450 Mediates Dopamine Formation in the Brain in Vivo","volume":"118","author":"Bromek","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein Measurement with the Folin Phenol Reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.bcp.2016.04.017","article-title":"The Reverse Role of the Hypothalamic Paraventricular (PVN) and Arcuate (ARC) Nuclei in the Central Serotonergic Regulation of the Liver Cytochrome P450 Isoform CYP2C11","volume":"112","author":"Rysz","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1007\/s00213-014-3673-4","article-title":"Proof-of-Concept Randomized Controlled Trial of Pregnenolone in Schizophrenia","volume":"231","author":"Marx","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3371\/CSRP.KRBA.013114","article-title":"Adjunctive Pregnenolone Ameliorates the Cognitive Deficits in Recent-Onset Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Trial","volume":"10","author":"Kreinin","year":"2017","journal-title":"Clin. Schizophr. Relat. Psychoses"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fpsyt.2018.00073","article-title":"Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications","volume":"9","author":"Cai","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fendo.2019.00169","article-title":"Neurosteroid Actions in Memory and Neurologic\/Neuropsychiatric Disorders","volume":"10","author":"Ratner","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/jnc.13031","article-title":"The Cytochrome P450 2D-Mediated Formation of Serotonin from 5-Methoxytryptamine in the Brain in Vivo: A Microdialysis Study","volume":"133","author":"Haduch","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_33","unstructured":"Stahl, S.M. (2013). Stahl\u2019s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, Cambridge University Press."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1080\/03602532.2018.1554674","article-title":"The Engagement of Brain Cytochrome P450 in the Metabolism of Endogenous Neuroactive Substrates: A Possible Role in Mental Disorders","volume":"50","author":"Haduch","year":"2018","journal-title":"Drug Metab. Rev."},{"key":"ref_35","unstructured":"De Luca, L.A., Menani, J.V., and Johnson, A.K. (2014). Brain Serotonergic Receptors and Control of Fluid Intake and Cardiovascular Function in Rats. Neurobiology of Body Fluid Homeostasis: Transduction and Integration, CRC Press\/Taylor & Francis. Frontiers in Neuroscience."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/bph.12906","article-title":"Dopamine Receptors\u2014IUPHAR Review 13","volume":"172","author":"Beaulieu","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.pharmthera.2017.10.008","article-title":"CYP-Mediated Drug Metabolism in the Brain Impacts Drug Response","volume":"184","author":"McMillan","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/03602532.2020.1858856","article-title":"Cytochrome P450 Expression and Regulation in the Brain","volume":"53","author":"Kuban","year":"2021","journal-title":"Drug Metab. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1016\/j.clinthera.2015.11.001","article-title":"Pharmacokinetics and Tolerability of Lurasidone in Children and Adolescents with Psychiatric Disorders","volume":"37","author":"Findling","year":"2015","journal-title":"Clin. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"112750","DOI":"10.1016\/j.biopha.2022.112750","article-title":"Impact of 5-HT7 Receptor Inverse Agonism of Lurasidone on Monoaminergic Tripartite Synaptic Transmission and Pathophysiology of Lower Risk of Weight Gain","volume":"148","author":"Fukuyama","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.mce.2010.08.014","article-title":"C\/EBP\u03b2 Is AMP Kinase Sensitive and up-Regulates PEPCK in Response to ER Stress in Hepatoma Cells","volume":"331","author":"Choudhury","year":"2011","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0014-5793(98)00746-7","article-title":"Re-Expression of C\/EBP Alpha Induces CYP2B6, CYP2C9 and CYP2D6 Genes in HepG2 Cells","volume":"431","author":"Jover","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1128\/MCB.00601-06","article-title":"Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor \u03b3","volume":"27","author":"Burgermeister","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2119\/molmed.2010.00063","article-title":"Phosphorylation of Extracellular Signal-Regulated Kinase (ERK)-1\/2 Is Associated with the Downregulation of Peroxisome Proliferator\u2013Activated Receptor (PPAR)-\u03b3 during Polymicrobial Sepsis","volume":"16","author":"Kaplan","year":"2010","journal-title":"Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuroscience.2018.03.009","article-title":"The Involvement of PPARs in the Selective Regulation of Brain CYP2D by Growth Hormone","volume":"379","author":"Zhang","year":"2018","journal-title":"Neuroscience"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/21\/3513\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:11:24Z","timestamp":1760145084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/21\/3513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,6]]},"references-count":45,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["cells11213513"],"URL":"https:\/\/doi.org\/10.3390\/cells11213513","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2022,11,6]]}}}