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Hlaing H Maw, Xingzhong Zeng, Scot Campbell, Mitchell E Taub, Aaron M Teitelbaum
BI 187004, an 11β-hydroxysteroid dehydrogenase 1 (HSD) inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite (M1) was 7 fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzyme(s) responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors...
March 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Cynthia A Kelm-Nelson, Michael A Trevino, Michelle R Ciucci
Parkinson disease (PD) related to homozygous mutations in the Pink1 gene is associated with nigrostriatal dopamine depletion and a wide range of sensorimotor deficits. In humans and animal models of PD, not all sensorimotor deficits are levodopa-responsive. We hypothesized that the underlying mechanisms of locomotion, limb control, and vocal communication behavior include other pathologies. Here, Pink1 -/- rats were treated with an oral dose of levodopa and limb motor and vocal communication behaviors were measured...
February 26, 2018: Neuroscience
Fernando Estévez-López, Daniel Camiletti-Moirón, Virginia A Aparicio, Víctor Segura-Jiménez, Inmaculada C Álvarez-Gallardo, Alberto Soriano-Maldonado, Milkana Borges-Cosic, Pedro Acosta-Manzano, Rinie Geenen, Manuel Delgado-Fernández, Luis J Martínez-González, Jonatan R Ruiz, María J Álvarez-Cubero
BACKGROUND: Candidate-gene studies on fibromyalgia susceptibility often include a small number of single nucleotide polymorphisms (SNPs), which is a limitation. Moreover, there is a paucity of evidence in Europe. Therefore, we compared genotype frequencies of candidate SNPs in a well-characterised sample of Spanish women with fibromyalgia and healthy non-fibromyalgia women. METHODS: A total of 314 women with a diagnosis of fibromyalgia (cases) and 112 non-fibromyalgia healthy (controls) women participated in this candidate-gene study...
February 27, 2018: Journal of Translational Medicine
Lauren D Hill, Margaret S Lorenzetti, Sarah M Lyle, Ana I Fins, Aurélien Tartar, Jaime L Tartar
Introduction: We tested the extent to which the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with affective state and evening cortisol levels. We limited our study to women as previous research suggests that the link between COMT genotype and psychological health is entangled by sex differences. Materials and Methods: The participants were assessed on measures of anxiety, mood disturbance, depressive symptomatology, and perceived stress...
February 2018: Brain and Behavior
Joel J Bruegger, Brian C Smith, Sarah L Wynia-Smith, Michael A Marletta
Cysteine S-nitrosation is a reversible posttranslational modification mediated by nitric oxide (·NO)-derived agents. S-nitrosation participates in cellular signaling and is associated with several diseases such as cancer, cardiovascular diseases, and neuronal disorders. Despite the physiological importance of this nonclassical ·NO signaling pathway, little is understood about how much S-nitrosation affects protein function. Moreover, identifying physiologically relevant targets of S-nitrosation is difficult because of the dynamics of transnitrosation and a limited understanding of the physiological mechanisms leading to selective protein S-nitrosation...
February 26, 2018: Journal of Biological Chemistry
Shraddha Sapkota, Roger A Dixon
BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein)...
2018: Journal of Alzheimer's Disease: JAD
Frédéric Aubrun, Noël Zahr, Olivier Langeron, Nicolas Boccheciampe, Nathalie Cozic, Lisa Belin, Jean-Sebastien Hulot, Frederic Khiami, Bruno Riou
BACKGROUND: Among the various factors that may influence the pharmacological response to opioids, genetic polymorphisms [single nucleotide polymorphisms (SNP)] have generated some interest. OBJECTIVES: To examine the influence on morphine dose requirements and adverse events in the postoperative period of four SNP [opioid receptor mu1 (OPRM1), ATP-binding cassette subfamily B, member 1 (ABCB1) ex-21 and ex-26, catechol-o-methyltransferase (COMT)] in candidate genes involved in morphine pharmacodynamics and pharmacokinetics...
February 22, 2018: European Journal of Anaesthesiology
Ramin Saravani, Hamid Reza Galavi, Marzieh Lotfian Sargazi
Objective: Several studies have shown that some polymorphisms of genes encoding catechol-O-methyltransferase (COMT), the key enzyme in degrading dopamine, and norepinephrine and the human brain-derived neurotropic factor (BDNF), a nerve growth factor, are strong candidates for risk of schizophrenia (SCZ). In the present study, we aimed at examining the effects of COMT Val158Met (G>A) and BDNF Val66Met (G>A) polymorphisms on SCZ risk in a sample of Iranian population. Method: This case- control study included 92 SCZ patients and 92 healthy controls (HCs)...
October 2017: Iranian Journal of Psychiatry
Amandine Valomon, Sebastian C Holst, Alessandro Borrello, Susanne Weigend, Thomas Müller, Wolfgang Berger, Michael Sommerauer, Christian R Baumann, Hans-Peter Landolt
Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans...
February 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Yikai Hu, Chenghu Li, Yangfan Wang, Qinhan Li, Yidong Liu, Shengde Liao, Peiqing Cao, Hongmei Xu
Schizophrenia is a severe mental disorder, and its mechanisms have not been fully elucidated. A functional single nucleotide polymorphism (SNP) present in the catechol-O-methyltransferase (COMT) gene, Val158Met (rs4680) (Chr22: 19,963,498), is possibly related to the violent behavior of schizophrenia patients. However, the specific variant that causes violent behavior is still unknown. Since the Val variation of Val158Met (rs4680) introduces a CG site into the sequence, the methylation level of the Val158Met (rs4680) region may also have an association with the homicidal behavior of schizophrenia patients...
February 17, 2018: International Journal of Legal Medicine
Aniket Magarkar, Petteri Parkkila, Tapani Viitala, Tatu Lajunen, Edouard Mobarak, Giuseppe Licari, Oana Cramariuc, Eric Vauthey, Tomasz Róg, Alex Bunker
The enzyme catechol-O-methyltransferase (COMT) has water soluble (S-COMT) and membrane associated (MB-COMT), bitopic, isoforms. Of these MB-COMT is a drug target in relation to the treatment of Parkinson's disease. Using a combination of computational and experimental protocols, we have determined the substrate selection mechanism specific to MB-COMT. We show: (1) substrates with preferred affinity for MB-COMT over S-COMT orient in the membrane in a fashion conducive to catalysis from the membrane surface and (2) binding of COMT to its cofactor ADOMET induces conformational change that drives the catalytic surface of the protein to the membrane surface, where the substrates and Mg 2+ ions, required for catalysis, are found...
February 15, 2018: Chemical Communications: Chem Comm
Chin-Hsien Lin, Jun-Yu Fan, Han-I Lin, Chia-Wen Chang, Yih-Ru Wu
OBJECTIVE: Catechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for both motor and cognitive functions. Few studies have examined the association between COMT variants and cognition in patients with Parkinson's disease (PD). METHODS: We assessed a cohort of 409 PD patients without dementia who were regularly followed for two years. The Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE) were administered at baseline and during the follow-up...
February 9, 2018: Parkinsonism & related Disorders
Anna V Kirenskaya, Zinaida I Storozheva, Marina A Gruden, Robert D E Sewell
Genetic influences modulating executive functions engaging prefrontal cortical brain systems were investigated in 141 male subjects. The effects of variations in two genes implicated in dopamine and GABA activities in the prefrontal cortex: rs4680 (Val158/Met polymorphism of the catechol-o-methyltransferase gene-COMT) and rs3749034 (C/T) substitution in the promoter region of the glutamic acid decarboxylase gene (GAD1) were studied on antisaccade (AS) performance in healthy subjects and schizophrenic patients...
February 10, 2018: European Archives of Psychiatry and Clinical Neuroscience
Ian G M Cameron, Deanna L Wallace, Ahmad Al-Zughoul, Andrew S Kayser, Mark D'Esposito
RATIONALE: The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility. OBJECTIVE: We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility...
February 9, 2018: Psychopharmacology
Mehmet Oezkur, Attila Magyar, Phillip Thomas, Andreas Reif, Stefan Störk, Peter U Heuschmann, Rainer G Leyh, Martin Wagner
BACKGROUND: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery...
February 9, 2018: BMC Nephrology
Yang-Liu Xia, Tong-Yi Dou, Yong Liu, Ping Wang, Guang-Bo Ge, Ling Yang
Daphnetin (7,8-dihydroxycoumarin (7,8-DHC)) and its C-4 derivatives have multiple pharmacological activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Methylation plays important roles in catechol elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of human catechol-O-methyltransferase (COMT) remain unclear. This study was aimed at exploring the structure-methylation relationship of daphnetin and its C-4 derivatives, including 4-methyl, 4-phenyl and 4-acetic acid daphnetin...
January 2018: Royal Society Open Science
Albert Batalla, Valentina Lorenzetti, Yann Chye, Murat Yücel, Carles Soriano-Mas, Sagnik Bhattacharyya, Marta Torrens, José A S Crippa, Rocío Martín-Santos
Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18-30 years...
2018: Cannabis and Cannabinoid Research
Anne Estrup Olesen, Debbie Grønlund, Mikkel Gram, Frank Skorpen, Asbjørn Mohr Drewes, Pål Klepstad
OBJECTIVE: Use of opioids for pain management has increased over the past decade; however, inadequate analgesic response is common. Genetic variability may be related to opioid efficacy, but due to the many possible combinations and variables, statistical computations may be difficult. This study investigated whether data processing with support vector machine learning could predict required opioid dose in cancer pain patients, using genetic profiling. Eighteen single nucleotide polymorphisms (SNPs) within the µ and δ opioid receptor genes and the catechol-O-methyltransferase gene were selected for analysis...
January 27, 2018: BMC Research Notes
Joseph P Schacht, Konstantin E Voronin, Patrick K Randall, Raymond F Anton
Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested...
December 6, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Sameh E Soliman, Crystal N D'Silva, Helen Dimaras, Irakli Dzneladze, Helen Chan, Brenda L Gallie
BACKGROUND: Children with retinoblastoma treated with carboplatin chemotherapy risk moderate to severe, irreversible hearing loss. Based on published evidence, we hypothesized that ototoxicity risk is associated with clinical parameters and variants in candidate genes in drug metabolism pathways (methyltransferases [thiopurine S-methyltransferase, TPMT] and [catechol-O-methyltransferase, COMT], and drug transporter ABCC3). PROCEDURE: We retrospectively reviewed clinical records of patients with retinoblastoma treated with carboplatin chemotherapy regarding age (at diagnosis and chemotherapy initiation), chemotherapy sessions (cycles number, drug doses, and cumulative carboplatin dose), and hearing loss (defined as ototoxicity ≥grade 2 by at least one classification system)...
January 19, 2018: Pediatric Blood & Cancer
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