Relation between CYP2D6 Phenotype and Genotype and Personality in Healthy Volunteers

González, Idilio; Peñas-Lledó, Eva; Pérez, Bárbaro Armas; Dorado, Pedro; Álvarez, Mayra; LLerena, Adrián

doi:10.2217/14622416.9.7.833

Cited by 66 publications

(36 citation statements)

References 31 publications

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“…[12][13][14] Specifically, the poor metabolizer phenotype is thought to be associated with an anxious personality trait. 15,16 However, no consistent phenotype has been detected in other studies. [17][18][19][20] Therefore, current knowledge of the role of CYP2D6 is limited to its biochemical function, but lacks any specification of an in vivo phenotype.…”

Section: Introductionmentioning

confidence: 85%

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CYP2D6 in the brain: genotype effects on resting brain perfusion

et al. 2010

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The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N = 188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N = 42 matched extensive metabolizers, N = 14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (P = 0.03 and 0.003). Effects were also present in the whole (N = 188) sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (P = 0.05). An exploratory analysis, extended to the whole brain, suggested the involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.

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Section: Introductionmentioning

confidence: 85%

“…15,16 The hippocampus has been shown to be involved in the regulation of anxiety. 57 However, only limited evidence was found for an effect of CYP2D6 activity on perfusion in this region.…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 in the brain: genotype effects on resting brain perfusion

et al. 2010

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“…CYP2D6 genetic polymorphisms studies have been carried out in Latin American countries supported by the CEIBA. FP Consortium of the Ibero-American Network of Pharmacogenetics & Pharmacogenomics (RIBEF) (de Andrés et al, 2013;Rodeiro et al, 2012), including Ecuadorians , Mexicans (Sosa-Macías, Dorado, Alanis-Bañuelos, Llerena, & Lares-Asseff, 2010) and Cubans (González et al, 2008;Llerena et al, 2013;Peñas-Lledó, Dorado, Pacheco, González, & Llerena, 2009). However, this will constitute the first report of a Costa Rican population including groups from different ethnic backgrounds.…”

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confidence: 99%

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

Céspedes-Garro

Jiménez-Arce

Naranjo

et al. 2014

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CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with

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“…Thus humanized CYP2D6 transgenic mice show a higher concentration of serotonin and its metabolite 5-HIAA in blood plasma (Yu et al, 2003) and the brain (Cheng et al, 2013), and intracerebral administration of 5-MT increases the extracellular concentration of serotonin in the brain, as has been shown using a brain microdialysis in living rats (Haduch et al, 2015). Moreover, individuals with no or a defective CYP2D6 gene (expressing a poor metabolizer phenotype) are more anxiety prone (Bertilsson et al, 1989;González et al, 2008;Cheng et al, 2013), such a behavior being provoked by a low serotonin level in the limbic system of the brain (Hensler, 2006).…”

Section: Discussionmentioning

confidence: 99%

Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain

Haduch

Bromek

Wójcikowski

et al. 2016

Drug Metabolism and Disposition

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Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)-lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine-lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.

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Relation between CYP2D6 Phenotype and Genotype and Personality in Healthy Volunteers

Cited by 66 publications

References 31 publications

CYP2D6 in the brain: genotype effects on resting brain perfusion

CYP2D6 in the brain: genotype effects on resting brain perfusion

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain

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