Endocrine Disrupting Compounds – Problems and Challenges

In this chapter, information about some of the estrogenic compounds and their environmental fate and biological influence can be found. Special attention is paid to the review of the analytical approaches used at the stages of detection and determination of Endocrine Disrupting Compounds (EDCs) in the environmental samples. Also, a brief characterization of both cellular and non-cellular bioassays is presented

Similarity between enzymatic and electrochemical oxidation of 2-hydroxyacridinone, the reference compound of antitumor imidazoacridinones.

The present work is part of a wide research project aimed to elucidate the mechanism of the metabolic activation of the antitumor imidazoacridinone agent C-1311 selected for clinical trials. The objectives of the investigations presented here were: (i) to examine the enzymatic transformation of the reference compound 2-hydroxyacridinone and (ii) to test the similarity between enzymatic and electrochemical oxidation of acridinone compounds. This similarity was searched with respect to the usefulness of the electrochemical results for further studies on the metabolic oxidation of imidazoacridinone antitumor drugs. The enzymatic oxidation of 2-hydroxyacridinone was performed with a model system containing various amounts of horseradish peroxidase and hydrogen peroxide and was followed by UV-VIS spectroscopy and by HPLC. One product of the reaction was isolated and its chemical structure was identified. It was shown that 2-hydroxyacridinone was transformed by the studied system in a manner dependent on the amount of the enzyme and on the compound/H2O2 ratio. While under mild reaction conditions the transformation ran slowly to yield only one product, p1, independently of the reaction time, higher enzyme concentration resulted in several steps of transformation. Product p1 turned out to be a dimer: 1,1-bi(2-hydroxyacridinone). A comparison of the results of the enzymatic transformations of 2-hydroxyacridinone presented here with studies on the electrochemical oxidation reported earlier allowed us to show both transformations to be similar as far as the reaction pathway and two reaction products are concerned

Binary Mixtures of Selected Bisphenols in the Environment: Their Toxicity in Relationship to Individual Constituents

Bisphenol A (BPA) is one of the most popular and commonly used plasticizer in the industry. Over the past decade, new chemicals that belong to the bisphenol group have increasingly been used in industrial applications as alternatives to BPA. Nevertheless, information on the combined effects of bisphenol (BP) analogues is insufficient. Therefore, our current study aimed to find the biological response modulations induced by the binary mixtures of BP compounds. We determined the toxicity levels in Microtox and XenoScreen YES/YAS assays for several BP analogs alone, and for their binary mixtures. The results obtained constituted the database for chemometric intelligent data analysis to evaluate the possible interactions occurring in the mixtures. Several chemometric/biophysical models have been used (concentration addition—CA, independent action—IA and polynomial regression calculations) to realize this aim. The best fitting was found for the IA model and even in this description strong evidence for synergistic behaviors (modes of action) of some bisphenol analogue mixtures was demonstrated. Bisphenols A, S, F and FL were proven to be of significant endocrine threat (with respect to XenoScreen YES/YAS assay); thus, their presence in mixtures (including presence in tissues of living organisms) should be most strictly monitored and reported

Metabolic transformations of antitumor imidazoacridinone, C-1311, with microsomal fractions of rat and human liver

The imidazoacridinone derivative C-1311 is an antitumor agent in Phase II clinical trials. The molecular mechanism of enzymatic oxidation of this compound in a peroxidase model system was reported earlier. The present studies were performed to elucidate the role of rat and human liver enzymes in metabolic transformations of this drug. C-1311 was incubated with different fractions of liver cells and the reaction mixtures were analyzed by RP-HPLC. We showed that the drug was more sensitive to metabolism with microsomes than with cytosol or S9 fraction of rat liver cells. Incubation of C-1311 with microsomes revealed the presence of four metabolites. Their structures were identified as dealkylation product, M0, as well as a dimer-like molecule, M1. Furthermore, we speculate that the hydroxyl group was most likely substituted in metabolite M3. It is of note that a higher rate of transformation was observed for rat than for human microsomes. However, the differences in metabolite amounts were specific for each metabolite. The reactivity of C-1311 with rat microsomes overexpressing P450 isoenzymes, of CYP3A and CYP4A families was higher than that with CYP1A and CYP2B. Moreover, the M1 metabolite was selectively formed with CYP3A, whereas M3 with CYP4A. In conclusion, this study revealed that C-1311 varied in susceptibility to metabolic transformation in rat and human cells and showed selectivity in the metabolism with P450 isoenzymes. The obtained results could be useful for preparing the schedule of individual directed therapy with C-1311 in future patients