Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia
Shusuke NumataShuichi UenoJun‐ichi IgaKen YamauchiHongwei SongSawako KinouchiSumiko Shibuya‐TayoshiShin’Ya TayoshiHirofumi AkiSatsuki SumitaniMitsuo ItakuraTetsuro Ohmori
26
Citation
35
Reference
10
Related Paper
Citation Trend
Catechol O-methyltransferase (COMT) obtained from human liver (HL) and human placenta (HP) was found to be much less active than rat liver (RL) COMT when norepinephrine, epinephrine, dopamine, and isoproterenol are used as substrates. The K m values, which reflect the affinity of substrate and enzyme, show that RL COMT has the highest affinity toward the catecholamine substrates followed by HP COMT and then HL COMT. Both HP and RL COMT preparations O-methylate the catecholamines primarily in the meta position.
Catechol
Cite
Citations (7)
The major detoxification pathway of the carcinogenic catechol estrogens is methylation by catechol-O-methyltransferase (COMT). It has been hypothesized that the enzyme encoded by the low-activity allele (COMTL) has a lower catalytic activity for catechol estrogen methylation than that encoded by the high activity allele (COMTH). We expressed and purified human soluble (S)-COMTH and S-COMTL in Escherichia coli and characterized the methylation of 2- and 4-hydroxyestradiol (2- and 4-OH-E2). There were no differences between the kinetic parameters for COMTH and COMTL. The kinetic parameters for S-adenosylmethionine (SAM), the methyl donor in these reactions, also did not differ for COMTH and COMTL. S-adenosylhomocysteine, the demethylated SAM metabolite, inhibited methylation of the catechol estrogens in a non-competitive manner similarly for COMTH and COMTL. Each COMT substrate tested inhibited the methylation of other substrates in a mixed competitive and non-competitive fashion similarly for COMTH and COMTL. Furthermore, in cytosolic fractions of COMTHH (MCF-10A and ZR-75–1) and COMTLL (MCF-7 and T47D) human breast epithelial cell lines, no differences were detected between the kinetic parameters of COMT with respect to 2- and 4-OH-E2 methylation; nor were COMT protein levels associated with the COMT genotype. These data suggest that the decreased COMT enzymatic activity that has been detected in human tissue in association with the COMTL allele is not reflected by differences in the affinity or capacity of COMTH and COMTL for catechol estrogen methylation. These results raise the question of what accounts for the difference in COMT activity associated with the COMTHH and COMTLL genotypes in human tissue.
Catechol
Cite
Citations (55)
Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val 108/158 Met) in the catechol- O -methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance ( P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups ( n = 11–16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
rs4680
Cite
Citations (2,408)
Sand, P. G.*; Korte, G.; Domani, M.; Konstandin, N.; Karl, A.; Wagner, K.; Dinnbier, M. Author Information
Pain tolerance
Cite
Citations (2)
Entacapone
Benserazide
Microdialysis
Catechol
Decarboxylase inhibitor
Cite
Citations (33)
Cite
Citations (0)
Catechol
Cite
Citations (41)
Catechol
rs4680
Cite
Citations (0)
Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task.In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences.Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.
rs4680
Cite
Citations (138)
Entacapone
Cite
Citations (16)