The Effect of Chronic Treatment with Lurasidone on Rat Liver Cytochrome P450 Expression and Activity in the Chronic Mild Stress Model of Depression

Abstract

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg per os per day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects CYP (CYP2B, CYP2C11, and CYP3A), and its effects are different from those observed after other kinds of psychologic stress, such as repeated restraint stress or early-life maternal deprivation; 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11, and CYP3A isoforms; and 3) CMS modifies the action of lurasidone on CYP expression and function, leading to different effects of the neuroleptic in nonstressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g., steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11, or CYP3A, may proceed at a different rate in the two groups of animals (nonstressed and stressed) in the rat CMS model.

Chaihu-Shugan-San Reinforces CYP3A4 Expression via Pregnane X Receptor in Depressive Treatment of Liver-Qi Stagnation Syndrome

“…The results indicate that posttranscriptional or posttranslational modifications occur to CYP450 produced in the liver, consistent with previous research [36].…”

“…CYP450 enzymes serve as the major enzyme system that regulates TCM metabolism [36, 42, 43]. Among this superfamily, CYP3A4 is a major isozyme that is highly expressed in the liver and is known to metabolize many different drugs; CYP3A4 is regulated by pregnane X receptor (PXR) [44, 45].…”

The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat

“…The protein levels of CYP1A, CYP2A, CYP2C11, CYP2B, CYP2D, CYP3A1/23 and CYP3A2 in the liver microsomes (10 µg of proteins) of control and antidepressant-treated rats were estimated by Western immunoblot analysis, as previously described [ 5 , 6 , 14 ]. Monoclonal anti-rat CYP2B and CYP2C6, polyclonal anti-rat CYP1A1, CYP2C11, CYP3A1/23 or CYP3A2 antibodies, anti-human CYP2A13 (reacting with rat CYP2A) and CYP2D6 (reacting with rat CYP2D) antibodies, and a secondary antibody (a species-specific horseradish peroxidase-conjugated anti-IgG) were used.…”

“…In summary, agomelatine and imipramine produced different broad-spectrum effects on cytochrome P450 expression and activity, which suggests the involvement of pharmacological mechanisms and formation of reactive metabolites in the enzyme regulation. CMS modified the effects of antidepressants, which might be caused by alterations in the function of the brain nervous system [61], affecting in this way peripheral glucocorticoids, catecholamines and cytokines and, in turn, hepatic signaling pathways [13,14,62,68]. Although CMS affected antidepressant effects on cytochrome P450 expression, the enzyme activity remained similar.…”

“…Stress-evoked changes in these systems may affect cytochrome P450 expression and activity and modify the effect of psychotropic drugs on the enzyme. Our recent studies have indicated that chronic mild stress (CMS) affects liver cytochrome P450 and modifies the action of the atypical neuroleptic lurasidone or the antidepressants venlafaxine and escitalopram, on cytochrome P450 in the liver or brain [14,15].…”