Catechol-O-methyl transferase

About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.

Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder.

Abstract: Objective: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression. Method: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin. Results: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed. Conclusions: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder. (Am J Psychiatry 1997; 154:113‐115)

The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases.

Abstract: The COMT inhibitors entacapone and tolcapone are rapidly metabolized in vivo, mainly by glucuronidation. In this work, the main UGT isoforms responsible for their glucuronidation in vitro were characterized by using a subset of representative cloned and expressed human UGT isoforms. Entacapone in particular was seen to be an exceptionally good substrate for UGT1A9 with an even higher reaction velocity value at 500 microM substrate concentration compared with that of the commonly used substrate, propofol (1.3 and 0.78 nmol min(-1) mg(-1), respectively). Neither entacapone nor tolcapone was glucuronidated by UGT1A6. Tolcapone was not detectably glucuronidated by UGT1A1, and the rate of glucuronidation of entacapone was also low by this isoform. However, UGT1A1 was the only UGT capable of catalyzing the formation of two glucuronides of the catecholic entacapone. Both COMT inhibitors were glucuronidated at low rates by the representative members of the UGT2B family, UGT2B7 and UGT2B15. Michaelis-Menten parameters were determined for entacapone and tolcapone using recombinant human UGT isoforms and human liver microsomes to compare the kinetic properties of the two COMT inhibitors. The kinetic data illustrates that UGT1A9 exhibited a much greater rate of glucuronidation and a far lower K(m) value for both entacapone and tolcapone than UGT2B15 and UGT2B7 whose contribution is minor by comparison. Entacapone showed a 3 to 4 times higher V(max) value and a 4 to 6 times lower K(m) value compared with those of tolcapone both in UGT1A9 cell lysates and in human liver microsomes.

Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome

Abstract: Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val158Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val158Met genotype impacts upon cognition in children with 22q11DS.

COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults.

Abstract: The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene–gene interactions that influence central dopaminergic systems. (JINS, 2011, 17, 1–7)