The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism.

Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin.

Cocaine-Induced Time-Dependent Alterations in Cytochrome P450 and Liver Function.

Cytochrome P450 is responsible for the metabolism of endogenous substrates, drugs and substances of abuse. The brain and nervous system regulate liver cytochrome P450 via neuroendocrine mechanisms, as shown in rodents. Cocaine exerts its addictive effects through the dopaminergic system, the functioning of which undergoes changes during its continuous use.

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.

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.

The impact of noradrenergic neurotoxin DSP-4 and noradrenaline transporter knockout (NET-KO) on the activity of liver cytochrome P450 3A (CYP3A) in male and female mice.

Background: Our earlier studies have shown that the brain noradrenergic system regulates cytochrome P450 (CYP) in rat liver via neuroendocrine mechanism. In the present work, a comparative study on the effect of intraperitoneal administration of the noradrenergic neurotoxin DSP-4 and the knockout of noradrenaline transporter (NET-KO) on the CYP3A in the liver of male and female mice was performed.

Methods: The experiments were conducted on C57BL/6J WT and NET male/female mice.

The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver.

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip.

The regulation of liver cytochrome P450 expression and activity by the brain serotonergic system in different experimental models.

: Cytochrome P450 (CYP) metabolizes vital endogenous (steroids, vitamins) and exogenous (drugs, toxins) substrates. Studies of the last decade have revealed that the brain dopaminergic and noradrenergic systems are involved in the regulation of CYP. Recent research indicates that the brain serotonergic system is also engaged in its regulation.

Cytochrome P450 expression and regulation in the brain.

The regulation of brain cytochrome P450 enzymes (CYPs) is different compared with respective hepatic enzymes. This may result from anatomical bases and physiological functions of the two organs. The brain is composed of a variety of functional structures built of different interconnected cell types endowed with specific receptors that receive various neuronal signals from other brain regions.

Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD.

The engagement of brain cytochrome P450 in the metabolism of endogenous neuroactive substrates: a possible role in mental disorders.

The current state of knowledge indicates that the cerebral cytochrome P450 (CYP) plays an important role in the endogenous metabolism in the brain. Different CYP isoenzymes mediate metabolism of many endogenous substrates such as monoaminergic neurotransmitters, neurosteroids, cholesterol, vitamins and arachidonic acid. Therefore, these enzymes may affect brain development, susceptibility to mental and neurodegenerative diseases and may contribute to their pathophysiology.

Disruption of glucocorticoid receptors in the noradrenergic system leads to BDNF up-regulation and altered serotonergic transmission associated with a depressive-like phenotype in female GR(DBHCre) mice.

Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the noradrenergic system, may evoke depressive-like behavior in female but not male mutant mice (GR(DBHCre) mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the noradrenergic system influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic system. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GR(DBHCre) mice on both the mRNA and protein levels.

Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver.

Background: Rat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate of testosterone 2α and 16α-hydroxylation.

Methods: The reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazodone - 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day), in the absence of antidepressants in vitro.

The brain dopaminergic system as an important center regulating liver cytochrome P450 in the rat.

This paper reviews evidence that changes in the functioning of the brain dopaminergic system affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A in the case of the tuberoinfundibular pathway or CYP1A and CYP3A in the case of the mesolimbic pathway), as well as blood plasma concentration of the respective pituitary hormones in the rat. Thus, the brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds through the dopaminergic D(2) receptors of the pituitary (activated by the tuberoinfundibular pathway) and the D(2) receptors of the nucleus accumbens (activated by the mesolimbic pathway and conveying a message from the nucleus accumbens to the paraventricular nucleus of the hypothalamus).

Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications.

The aim of the present study was to investigate the influence of activation of brain dopaminergic system by different dopaminomimetics on the level and activity of liver cytochrome P450 (CYP) isoforms. Studies into the identification of hormones and cytokines which are known to mediate liver CYP expression were also simultaneously carried out. Stimulation of dopaminergic receptors in the pituitary, a target for the tuberoinfundibular pathway, by dopamine (a D(1)/D(2) receptor agonist) administered intraperitoneally caused a significant increase in the activities and protein levels of CYP2B, CYP2C11 and CYP3A, a substantial increase in the blood plasma level of growth hormone (GH) and a significant decrease in triiodothyronine (T(3)) level.

Brain levels of dextromethorphan and the intensity of opioid withdrawal in mice.

Consistent with their antagonistic actions at N-methyl-D-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM.

The regulation of liver cytochrome p450 by the brain dopaminergic system.

Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system.

The influence of long-term treatment with psychotropic drugs on cytochrome P450: the involvement of different mechanisms.

This paper emphasises that besides the direct action of psychotropic drugs on cytochrome P450 (CYP) (i.e., the binding of the parent drug to the enzyme) indirect mechanisms of CYP-psychotropic interactions, namely the formation of CYP-reactive metabolite complexes and their influence on enzyme regulation, are also very important.

Disposition of 1,2,3,4,-tetrahydroisoquinoline in the brain of male Wistar and Dark Agouti rats.

Direct evidence for accumulation of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance suspected of producing Parkinsonism in humans, has not yet been shown. This study aimed to examine TIQ disposition in the whole rat brain and in the striatum and substantia nigra (SN). TIQ was administered to male Wistar and Dark Agouti rats (20, 40 and 100 mg/kg i.