Estrogenic Phenol and Catechol Metabolites of PCBs Modulate Catechol-Omethyltransferase Expression Via the Estrogen Receptor: Potential Contribution to Cancer Risk

Abstract

Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.

Hepatocellular carcinoma and the risk of occupational exposure

“…Other studies in workers exposed to the PCB have reported an increased incidence of liver tumors [185][186][187][188] . Some possible mechanisms by which PCB can cause cancer have been assumed: Reactive oxygen species (ROS) is produced through the enzymatic oxidation or autoxidation of PCB; PCB determines the increased expression of genes responsible for inflammation and apoptosis in the liver; and PCB has "toxic" effects on certain genes, such as the loss of part of a chromosome and chromosome breakage [189][190][191][192][193][194][195][196][197][198][199] . ROS are also able to reduce telomerase activity which can determine telomere shortening.…”

Biological and social influences on cognitive control processes dependent on prefrontal cortex

“…Yet estrogen downregulates human COMT transcription in a dose- and time-dependent manner (Ho et al, 2008; Jiang et al, 2003; Xie et al, 1999) and results in COMT enzymatic activity being 30% lower in women than men (Boudikova et al, 1990; Chen et al, 2004; Cohn and Axelrod, 1971). The story that being homozygous for Met at codon 158 of COMT confers a cognitive advantage is not true for women during the portion of their menstrual cycle when their estrogen levels are high.…”

Polychlorinated Biphenyls and Polybrominated Biphenyls

“…For example, PCBs induce CYPs in the liver, which may redirect the metabolism of endogenous estrogen to more harmful estrogen catechols (Ho et al, 2008), or generate ROS that produce estrogen quinones .…”