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The isoflavone irilone is found in human plasma after ingestion of red clover-based dietary supplements, but information allowing safety assessment is rare. Here, data in support of the mutagenic potential of irilone in cultured V79 cells [1] are presented. These data include (i) a quantitative assessment of irilone in the culture medium during the cell culture experiments, (ii) changes in the mutation spectrum in cDNA of the hypoxanthine-guanine phosphoribosyltransferase locus of irilone-treated V79 cells, (iii) occurrence of karyorrhexis and apoptosis as well as (iv) number of micronucleated cells containing whole chromosomes or chromosomal fragments. Also exemplary micrographs, used for the fluorescence microscopic assessment of (iii) and (iv) are presented.

The tissue concentrations of the female sex hormone 17β-estradiol (E2) and its reactive catechol metabolites such as 4-hydroxyestradiol (4-HO-E2) play important roles in hormonal carcinogenesis. They are influenced by the activity of local enzymes involved in the metabolic activation and inactivation of E2. In the mammary gland, catechol estrogens are predominately inactivated by catechol-O-methyltransferase (COMT). Food supplements containing the soy isoflavones genistein and daidzein are consumed because they are believed to protect from breast cancer; however, this proposed benefit is controversial. The aim of the present study was to investigate the influence of soy isoflavones on the gene expression and activity of COMT in cultured human mammary adenocarcinoma MCF-7 cells. Levels of COMT messenger RNA (mRNA) were determined by reverse transcription/competitive polymerase chain reaction and COMT activity was determined by high-performance liquid chromatography analysis of the methylation products of both the model substrate quercetin and the physiological relevant substrate 4-HO-E2. Our study demonstrates for the first time that soy isoflavones at hormonally active concentrations cause a significant reduction of both COMT mRNA levels and COMT activity as well as of the methylation of 4-HO-E2. Experiments using the estrogen receptor (ER) antagonist ICI 182,780 support a role of the ER in the isoflavone-induced down-regulation of COMT expression. Thus, this study not only demonstrates that hormonally active concentrations of soy isoflavones inhibit the detoxification of catechols in this human breast cancer cell line but also implies that diet might influence COMT activity to a greater extent than heretofore recognized. [ABSTRACT FROM AUTHOR]

4-Monochlorobiphenyl (PCB3) is a component of commercial polychlorinated biphenyl (PCB) products and is an airborne environmental pollutant. Our recent study with transgenic Fischer 344 rats revealed the mutagenic potential of PCB3 in the livers of male rats. PCB3 is converted in vitro to hydroxylated metabolites, to hydroquinones (HQs, e.g., 2′,5′-HQ and 3′,4′-HQ), and can be further oxidized to quinones (Qs, e.g., 2′,5′-Q and 3′,4′-Q). This raises the question whether the mutagenic potential of PCB3 is due to the mutagenicity of PCB3 itself or of one of the metabolites. In this study, we investigated the mutagenicity of PCB3, of the monohydroxylated metabolites 2′-hydroxy (HO)-, 3′-HO-, and 4′-HO, of the HQs 3′,4′-HQ and 2′,5′-HQ and of the Qs 3′,4′-Q and 2′,5′-Q in cultured Chinese hamster V79 cells. The induction of gene mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene locus by selection with 6-thioguanine. The induction of chromosome and genome mutations was assessed using the micronucleus assay and immunochemical differentiation of micronuclei containing whole chromosomes (kinetochore positive) and DNA fragments (kinetochore negative). The induction of chromosome and genome mutations, detected as micronuclei, was only observed at higher, cytotoxic concentrations of monohydroxylated, catecholic, and quinoid metabolites of PCB3. However, both PCB3-Qs induced a significant increase in the mutant frequency of the hprt gene and did so at submicromolar concentrations. Thus, the present study demonstrates for the first time the mutagenicity of PCB3 metabolites in mammalian cells and identifies quinoid metabolites of PCB3 as potential ultimate mutagens. [ABSTRACT FROM AUTHOR]