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

Abstract

The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug–drug interactions.

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.…”

Aryl Hydrocarbon Receptor Involvement in the Sodium-Dependent Glutamate/Aspartate Transporter Regulation in Cerebellar Bergmann Glia Cells

“…Glu-gated ion channels, known as ionotropic Glu receptors (GRI), are responsible for fast excitatory neurotransmission, whereas metabotropic Glu receptors (GRM) mediate slower excitatory signals . Both subtypes of receptors have been characterized in neurons and in glial cells as well as in other tissues besides the Central Nervous System (CNS) . A membrane-to-nuclei Glu signaling is involved in transcriptional gene expression regulation, whereas a Glu-dependent increase in cytoplasmic Ca 2+ participates in translational control. , Ionotropic receptors are grouped in terms of their specific agonists in N -methyl- d -aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropoionic acid (AMPA), and Kainate (KA) receptors.…”