The Val158Met polymorphism in COMT gene and cancer risk: role of endogenous and exogenous catechols

Abstract

Catechol-O-methyltransferase, COMT, is an important phase II enzyme catalyzing the transfer of a methyl-group from S-adenosylmethionine to a catechol-containing substrate molecule. A genetic variant Val158Met in the COMT gene leads to a several-fold decrease in the enzymatic activity giving rise to the accumulation of potentially carcinogenic endogenous catechol estrogens and their reactive intermediates and increasing thus the risk of tumorigenesis. However, numerous association studies between the COMT genotype and susceptibility to various malignancies have shown inconsistent and controversial findings indicating that additional gene-gene and gene-environment interactions might be crucial in modulating the physiological role of the COMT. In this review article, the important contribution of dietary catechol-containing flavonoids to modification of the relationships between the COMT genotype and cancer risk is discussed. Whereas, the diverse anticancer activities of common phytochemicals, such as green tea polyphenols, quercetin, fisetin or luteolin, can be markedly changed (both decreased or increased) by the COMT-mediated O-methylation of these exogenous substrates, flavonoids can also behave as potent inhibitors of the COMT enzyme slowing detoxification of endogenous catechol estrogens. Such a many-featured functioning of the COMT and its complex regulation by several different genetic and environmental factors, including plant-based food ingredients, emphasizes the necessity to further stratify the association studies between the COMT genotype and tumor risk by consumption of catechol-containing dietary flavonoids. Currently, it can be only speculated that some of the possible associations might be masked by the regular intake of specific food polyphenols, taking effect in certain communities or populations.

Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer

“…To our knowledge, there are no studies reporting on the relationship between COMT and progression of NMIBC. Studies on association between COMT genotypes and various malignancies have shown inconsistent findings, indicating that additional interactions (gene–gene and gene–environment interactions) might modulate the role of the COMT [58]. Likewise, in our study it was the interaction of COMT (ValVal genotype) with MnSOD (ValVal genotype) rather than COMT alone that showed a significant impact, protecting from progression to muscle-invasive bladder cancer.…”

“…By catalyzing the methylation of various endobiotic and xenobiotic substances, COMT might protect DNA from damage [58]. In 1995 Lotta et al [59] identified in the COMT gene (at codon 108) a guanine (G) to adenine (A) transition that leads to the aminoacid substitution from valine (Val) to methionine (Met).…”

Cytotoxic action of methylquercetins in human lung adenocarcinoma cells

“…One reason for this is the very limited commercial availability of metabolites for experimental testing. There are three major types of metabolic derivatives of flavonoids formed as a consequence of enzymatic conjugation with methyl-, sulfate-or glycuronyl groups in the small intestine and liver catalyzed by COMT, sulfotransferase (SULT) or UDP-glucuronosyltransfrease (UGT), respectively (19,20,42). Considering some structural modification Table I.…”

“…One of the most important metabolic pathways that flavonoids undergo in the small intestine and liver is their methylation catalyzed by catechol-O-methyltransferase (COMT) (20). This phase II enzyme catalyzes the transfer of a methyl moiety from S-adenosylmethionine donor substance to a catecholic substrate, such as flavonoids (21).…”

Change of COMT Val158Met Genotype in Tumoral B Cells of a Chronic Lymphocytic Leukemia Patient: A Case Report

“…DNA was separated from whole blood sample, B cells and non-B fraction of PBMCs using QIAamp DNA Mini Kit (Qiagen) and the respective concentrations were determined by NanoDrop 2000C spectrophotometer (Thermo Scientific). Because of the recent increasing interest in possible role of phase II enzymes and their genetic variants in carcinogenesis [1], the fourth exon of catechol-O-methyltransferase (COMT) gene was amplified by polymerase chain reaction (PCR) and the COMT Val158Met (rs4680, G>A) genotype was determined by restriction analysis using FastDigest NIaIII (Hin1II, Thermo Scientific) as the restriction enzyme. …”