The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat
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ARTICLE
The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat Anna Haduch1 · Ewa Bromek1 · Marta Rysz1 · Renata Pukło1 · Mariusz Papp2 · Piotr Gruca2 · Magdalena Łasoń2 · Monika Niemczyk2 · Władysława A. Daniel1 Received: 23 April 2020 / Revised: 10 July 2020 / Accepted: 27 July 2020 © The Author(s) 2020
Abstract Background The aim of our research was to determine the effects of chronic treatment with the atypical antidepressant agomelatine on the expression and activity of liver cytochrome P450 (CYP) in the chronic mild stress (CMS) model of depression, and to compare the results with those obtained for the first-generation antidepressant imipramine. Methods Male Wistar rats were subjected to CMS for 7 weeks. Imipramine (10 mg/kg ip/day) or agomelatine (40 mg/kg ip/ day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3–7 of CMS). The levels of cytochrome P450 mRNA, protein and activity were measured in the liver. Results Agomelatine and imipramine produced different broad-spectrum effects on cytochrome P450. Like imipramine, agomelatine increased the expression/activity of CYP2B and CYP2C6, and decreased the CYP2D activity. Unlike imipramine, agomelatine raised the expression/activity of CYP1A, CYP2A and reduced that of CYP2C11 and CYP3A. CMS modified the effects of antidepressants at transcriptional/posttranscriptional level; however, the enzyme activity in stressed rats remained similar to that in nonstressed animals. CMS alone decreased the CYP2B1 mRNA level and increased that of CYP2C11. Conclusion We conclude the following: (1) the effects of agomelatine and imipramine on cytochrome P450 are different and involve both central and peripheral regulatory mechanisms, which implicates the possibility of drug–drug interactions; (2) CMS influences the effects of antidepressants on cytochrome P450 expression, but does not change appreciably their effects on the enzyme activity. This suggests that the rate of antidepressant drug metabolism under CMS is similar to that under normal conditions. Keywords Chronic mild stress (CMS) · Agomelatine · Imipramine · Liver · Cytochrome P450 expression · Cytochrome P450 activity
Introduction Cytochrome P450 (CYP) enzymes play an important role in the oxidative metabolism of endogenous substances (e.g. steroids, arachidonic acid, vitamins) and exogenous compounds including drugs. The physiological expression of liver cytochrome P450 is regulated via the hormonal and * Władysława A. Daniel nfdaniel@cyf‑kr.edu.pl 1
Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31‑343 Kraków, Poland
Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31‑343 Kraków, Poland
2
immune systems [1]. Our earlier studies showed an important role of the brain dopaminergic [2], noradrenergic [3, 4] and serotonergic [5–9] systems in the physiological neuroendocrine regulation of cytochrome P450
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