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Pharmacological Characterization of 5-Hydroxytryptamine Receptors in the Gastrointestinal Tract
Published in T.S. Gaginella, J.J. Galligan, SEROTONIN and GASTROINTESTINAL FUNCTION, 2020
Jeremy D. Gale, Keith T. Bunce
Recently, a novel 5-HT receptor has been described on myenteric ganglia isolated from guinea pig small intestine.155 The precise pharmacological profile of this receptor has yet to be completed, but it appears to be positively coupled to adenylyl cyclase. 5-HT, DOI, 5-CT, renzapride, and 5-methoxytryptamine were all active as agonists, although 5-CT and DOI were only weakly active. Sumatriptan and 8-OH-DPAT were inactive. The effects of these agonists were resistant to blockade by spiperone, methysergide, methiothepin, and tropisetron, excluding the involvement of 5-HT1, 5-HT2, and 5-HT4 receptors. Of the antagonists examined, only ketanserin (at concentrations of 10 μM) antagonized the effects of 5-HT, 5-methoxytryptamine, and DOI. The effects of renzapride were unaffected, suggesting a separate mechanism of action for this compound. This profile of activity might suggest the involvement of 5-HT2 receptors. However, both spiperone and methysergide were inactive as antagonists, and both compounds have high activity as antagonists of 5-HT2 receptors (see above). Furthermore, DOI was only a weak agonist and ketanserin was significantly less potent as an antagonist than would be expected at 5-HT2 receptors. To corroborate this conclusion, the authors examined the myenteric ganglia for mRNA coding for the 5-HT2 receptor; no such mRNA was detected. Once again, the receptor mediating these effects appears to be of a previously unknown subtype.
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
5-Methoxytryptamine is also present in trace amounts in the central nervous system, and it appears to have a biological significance since it alters behavior and modifies the brain chemical composition. It is probably derived from the neurotransmitter 5-hydroxytryptamine and S-adenosylmethionine by methylation (Figure 29). Deacetylation of 5-methoxy-N-acetyltryptamine also occurs in the brain, but this is probably a relatively minor pathway. 5-Methoxytryptamine is a potential precursor in the biosynthesis of 5-methoxymonomethyl or dimethyltryptamine. These N-methylated indoles may play a role in some psychiatric disorders (Figure 30).
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2D6 is expressed at low levels but constitutively in human brain (Chinta et al. 2002; Miksys et al. 2002), raising the possibility of an endogenous function of CYP2D6 in the metabolism of neurochemicals. CYP2D-dependent dextromethorphan O-demethylase activity has been well described in rat brain tissues (Tyndale et al. 1999). A study using the CYP2D6-humanized mouse line has established that CYP2D6 is a 5-methoxyindolethylamine O-demethylase (Yu et al. 2003c) and 5-methoxytryptamine, a metabolite and precursor of melatonin (N-acetyl-5-methoxytryptamine), is metabolized by CYP2D6 to 5-hydroxytryptamine (5-HT/serotonin) with a high turnover of 51.7 min−1 and a relatively low Km of 19.5 μM (Figure 3.116) (Yu et al. 2003b). 5-HT is usually synthesized from tryptophan by hydroxylation and decarboxylation. 5-HT can be converted to melatonin via NAT and 5-hydroxyindole-O-methyltransferase. The production of 5-HT from 5-methoxytryptamine by CYP2D6 is significantly inhibited by SSRIs such as fluoxetine, nor-fluoxetine, fluvoxamine, and citalopram (Yu et al. 2003b). Liver microsomes prepared from CYP2D6-transgenic mice exhibit ~16-fold higher 5-methoxytryptamine O-demethylase activity than that from the wild type. Coadministration of 5-methoxytryptamine and pargyline increases serum 5-HT level approximately threefolds in human CYP2D6-transgenic mice than the wild type (Yu et al. 2003b). It appears that the CYP2D6-mediated 5-methoxytryptamine O-demethylation affects serotonin production and thus influences a range of neurophysiologic functions.
Analysis of Lithuanian CYP2D6 polymorphism and its relevance to psychiatric care of the local population
Published in Nordic Journal of Psychiatry, 2019
Edgaras Dlugauskas, Robertas Strumila, Aiste Lengvenyte, Laima Ambrozaityte, Evelina Dagyte, Alma Molyte, Alvydas Navickas, Algirdas Utkus
Furthermore, CYP2D6 enzyme is present not only in the liver, but also in the brain [13]. Previous research has shown that this enzyme is involved in endogenous metabolism of neuroactive substances such as dopamine synthesis from tyramine [14] and regeneration of serotonin from 5-methoxytryptamine [15]. Some studies suggest that CYP2D6 activity levels may be related to certain personality traits [16] and psychiatric disorders [17,18]. In reference to suicide, CYP2D6 ultrarapid metabolizers have been demonstrated to be more frequent among people who had attempted [19,20] or successfully committed [21] suicide than in the general population. Therefore, the variation of CYP2D6 across populations may contribute not only to difference in drug safety and efficacy profiles, but also in the occurrence of mental health problems.
The engagement of brain cytochrome P450 in the metabolism of endogenous neuroactive substrates: a possible role in mental disorders
Published in Drug Metabolism Reviews, 2018
Anna Haduch, Władysława Anna Daniel
In vitro study with brain microsomes provided the first evidence for the hypothesis that the O-demethylation of 5-methoxytryptamine to serotonin may proceed in the brain (Haduch et al. 2013b). This reaction occurred in the microsomes from various rat brain regions, like limbic structures (e.g. the frontal cortex, the hippocampus) and the cerebellum, containing the highest amount of CYP2D. The O-demethylation of 5-methoxytryptamine was inhibited by specific CYP2D inhibitors, indicating that it is catalyzed by this enzyme. Screening studies on recombinant major CYP isoforms confirmed that isoforms of CYP2D1/2 and the main brain CYP2D isoform CYP2D4/18, are the main CYP enzymes responsible for biotransformation of 5-MT to serotonin in the rat. Interestingly, it was observed that human CYP2D6 is more efficient at catalyzing 5-MT O-demethylation to serotonin than the rat CYP2D isoforms. Therefore, a stronger positive effect of CYP2D6 in the human brain on the level of serotonin and indirectly on the level of melatonin seems to be very likely. Both indoleamines are of antidepressant significance, which underlines the importance of CYP2D for normal brain function.
Blood biomarkers and treatment response in major depression
Published in Expert Review of Molecular Diagnostics, 2018
Cristina Mora, Valentina Zonca, Marco A. Riva, Annamaria Cattaneo
One of the first metabolomic studies in the field of depression and treatment response was carried out by Kaddurah-Daouk and coworkers [145,151] who interrogated baseline metabolite profiles as possible markers associated with a future response to sertraline, or placebo and biomarkers associated with both placebo and sertraline. The authors used an LCECA platform and found a panel of metabolites specifically in responders as compared to nonresponder. As an example, they found that a decrease in 5-methoxytryptamine and an increase in arachidonic acid and α-ketoglutarate levels after 1 week of sertraline treatment were associated with a reduction in symptoms. Four weeks of treatment with sertraline were also associated with decreased levels of lactic acid, BCAAs, valine, leucine, and isoleucine.