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

Abstract

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′-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.

The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain

“…However, detail mechanisms by which drugs affect CYP2D protein levels in the brain have not been recognized so far. Our recent studies indicated similar effects of three atypical neuroleptics, asenapine, iloperidone and lurasidone, acting mainly as antagonists of dopaminergic D2 receptors and serotonergic 5-HT2/6/7 receptors, which affected the CYP2D activity/protein level in different brain regions (e.g., both drugs evoked a decrease in the frontal cortex and cerebellum, but increased it in the striatum) [ 27 , 38 , 39 ]. The changes produced by these three neuroleptics in brain CYP2D were different from and usually opposite to those found in the present work for the potential antidepressant CP-101,606.…”

“…Recent studies have shown that prolonged administration of some antidepressant and neuroleptic drugs affects CYP2D activity in brain structures involved in depression and schizophrenia (respectively), and influences the therapeutic action or side effects of those drugs (reviewed by [ 3 ]). Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances in the brain, changes in their activity may modify the pharmacological action of psychotropics, as recently suggested for the investigated antidepressants (e.g., escitalopram, venlafaxine) and atypical neuroleptics (e.g., asenapine, iloperidone and lurasidone) [ 15 , 27 , 37 , 38 , 39 ]. The abovementioned three atypical neuroleptics evoked similar pattern of changes in the regional CYP2D activity in the brain, which was different from that of antidepressants, and suggested the involvement of pharmacological (receptor) mechanisms.…”

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

“…Hence, it may be expected that in the human brain, CYP2D6 has a beneficial effect on the physiological level of active indoleamines, such as serotonin, melatonin and 5-methoxytryptamine. The role of CYP2D6 in the brain may be significant when the classical route of serotonin synthesis governed by tryptophan hydroxylase 2 (TPH2) is impaired [ 50 , 51 ] and/or when the CYP2D gene is duplicated or amplified ( CYP2D6*2 gene variant) or when CYP2D activity is modified by such inducers as alcohol or nicotine [ 43 , 52 , 53 , 54 , 55 ] or by psychotropic drugs, such as antidepressants [ 56 , 57 , 58 , 59 , 60 ] or neuroleptics [ 56 , 61 , 62 , 63 , 64 ]. The brain serotoninergic system has been shown to be involved in the pathophysiology of psychiatric disorders (depression, anxiety, schizophrenia) as well as in the mechanism of action of psychotropics, including antidepressants, anxiolytics or antipsychotics, respectively.…”