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.

Multiple promoters of catechol-O-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer

Abstract: Catechol-O-methyltransferase (COMT) plays an important role in estrogen-induced cancers because COMT inactivates catechol estrogens that have cancer-promoting activities. Two promoters control the expression of human COMT isoforms: membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT). We hypothesize that inactivation of MB-COMT and S-COMT is important in understanding the pathogenesis of endometrial cancer. To test this hypothesis, we investigated the methylation status and expression of two COMT isoforms in 4 endometrial cancer cell lines, 60 endometrial cancer tissues, 10 normal endometrium tissues from normal healthy controls, and 32 pairs of cancerous and normal endometrial samples from the same patients using methylation-specific PCR, methylation-specific sequencing, reverse transcription-PCR, and 5'-rapid amplification of cDNA ends. The results of this study clearly demonstrate that MB-COMT was inactivated and methylated, although S-COMT was activated and unmethylated in all endometrial cancer cell lines. The 5-aza-2'-deoxycytidine treatment restored MB-COMT expression in all cell lines. The promoter for MB-COMT was methylated in 47 of 60 cancer tissues but was unmethylated in endometrial tissues from cases without cancer. The promoter for S-COMT was unmethylated in all endometrial cancerous and normal tissues. The CpG methylation density at the MB-COMT promoter was significantly higher in cancer tissues (a mean of 79.1% of the 19 CpG sites; range, 69-94%) than in adjacent normal tissues (a mean of 8.7% of the 19 CpG sites; range, 3-14%). In summary, these findings demonstrate that methylation of multiple promoters of the COMT gene can selectively inactivate MB-COMT and may contribute to endometrial carcinogenesis.

Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.

Abstract: Preeclampsia is a leading cause of perinatal morbidity and mortality This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor Variations in MTHFR have been associated with preeclampsia By accounting for allelic variation in both genes, the role of COMT has been clarified COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity We tested for association between COMT haplotypes and the MTHFR 677 C→T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0004), and that risk increased linearly from low to high activity haplotypes (P = 0003) In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p = 0022) We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0052) and the fetal risk alleles in combination with a maternal balancing allele (P<0001) This non-random distribution was not observed in controls (P = 0341 and P = 0219, respectively) Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR

Prefrontal dysfunction in schizophrenia controlling for COMT val158met genotype and working memory performance

Abstract: Earlier studies with functional imaging in schizophrenia have demonstrated dysfunction of the dorsolateral prefrontal cortex during working memory. Controlling for behavioral performance and for catechol-O-methyltransferase (COMT) Val158Met genotype, we here demonstrate in a functional magnetic resonance imaging paradigm that patients recruit greater neuronal resources in prefrontal cortex during working memory, suggesting that this phenotype is a core functional trait of the disease. We also replicated earlier findings that the Val allele of the COMT polymorphism is associated with greater engagement of the prefrontal cortex.