The most consistent associations of with placebo responses are in pain-related studies. supplements used to prevent and treat these conditions are influenced by COMT in these four disease domains. Next, we discuss how COMT genetic variation influences the placebo response. We continue by discussing the possibility that genetic interactions may lead to different responses in Cilastatin the drug and placebo arms of randomized controlled trials?(RCTs), and?thereby distort or confound the outcomes. We argue that including the disease Cilastatin and placebo axes with the geneCdrug axis in pharmacogenomics has the potential to advance drug development Cilastatin and clinical care. Catechol-O-methyltransferase in form & function COMT is usually a Phase II enzyme (EC2.1.1.6) which, in the presence of magnesium ions, transfers a methyl group from S-adenosylmethionine (SAM) to a hydroxyl group around the catechol ring of endogenous and xenobiotic catechol substrates (Physique?1) [1]. During COMT-catalyzed O-methylation, SAM is usually converted to a competitive inhibitor, S-adenosylhomocysteine (SAH), resulting in a unfavorable feedback regulatory loop. The endogenous substrates of COMT include the catecholamine neurotransmitters and the hormones dopamine, norepinephrine, and epinephrine (Table?1) [2]. In the absence of methylation, these catecholamines can accumulate and generate semiquinone and quinone free radicals, which promote DNA and lipid damage [3]. Hence, COMT is an important detoxifier of reactive molecules and can protect cells from oxidative stress known to influence neurodegenerative and cardiometabolic disease and cancer (Physique?1). Open in a separate window Physique 1. Catechol-O-methyltransferase enzymatic functions.COMT is a Phase II enzyme that, in the presence of magnesium ions, transfers a methyl group (CH3) from SAM to the hydroxyl group of catechol-containing COMT substrates. SAM is usually thus converted to SAH, a competitive inhibitor of COMT. Endogenous substrates of COMT include the catecholamines, dopamine, epinephrine, and norepinephrine and the catechol-containing metabolic product of estrogen, catechol estrogen. COMT: Catechol-O-methyltransferase; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine. Table 1. Catechol-O-methyltransferase endogenous catechol substrates, Cilastatin their receptors and function. gene The gene is located on chromosome 22q11.2 and contains six exons that encode membrane and soluble forms of the enzyme. is usually ubiquitously expressed with the highest levels in the adrenal gland, liver, lung, ovary, urinary bladder, and placenta [7]. Whereas the soluble form is dominant in most tissues, the membrane form is dominant in the brain. Sexual dimorphism in expression has been attributed to its regulation by estrogen and its role in estrogen metabolism [8,9]. expression also varies with age, increasing in the liver tenfold from infancy to adulthood and then decreasing with age [10]. A three megabase deletion in chromosome 22q11.2, which includes the gene, results in DiGeorge/velocardiofacial syndrome [11]. The manifestations of this syndrome, including higher rates of schizophrenia, and susceptibility to cardiovascular disease and cancer, cross many organ systems, and are thought to arise in part because of loss of and its role in catecholamine metabolism and detoxification of reactive oxygen species. The most widely studied polymorphism, rs4680 (val158/108met), encodes a G (valine) to A (methionine) transition in exon 4 at codon 158 in the membrane, and 108 in the soluble form [12]. This polymorphism results in a three- to fourfold reduction in thermostability and enzymatic activity, and a commensurate increase in circulating catecholamines in individuals homozygous for the methionine (met/met) versus valine (val/val) form of the enzyme [13]. Rs4680 is usually a commonly occurring variant, with minor allele frequencies that vary by population ancestry but allow for powerful genetic analysis even in small studies. For example, the frequencies of the val-allele among samples of people of European, African, Rabbit Polyclonal to SH3GLB2 and Asian ancestry are 0.48, 0.69, and 0.62, respectively [14]. Although most studies focus on rs4680 owing to its functional consequences, the linked synonymous polymorphism rs4818 has also been shown to have clinical phenotypes [15,16], and haplotypes have been studied in schizophrenia [17] and pain [15,16]. & disease effects on executive function & neuropsychiatric symptoms COMT accounts for most of the dopamine clearance in the prefrontal cortex, where monoamine oxidases and dopamine transporters are poorly expressed [18]. Cilastatin Hence, higher order cognitive functions and behavioral endophenotypes modulated in the prefrontal cortex are more directly influenced by variations in the levels of COMT activity than other regions of the brain. The prefrontal cortex is responsible for a set of cognitive processes that mediate executive function. Although.