Authors:Jason Matthews; Shaimaa Ahmed Pages: 1 - 38 Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Jason Matthews, Shaimaa Ahmed The aryl hydrocarbon receptor (AHR) and estrogen receptors (ERs) are ligand-activated transcription factors and members of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) and nuclear receptor (NR) superfamilies, respectively. The bHLH-PAS and NRs regulate many vital physiological processes including metabolism, circadian rhythm, differentiation, development, and reproduction. However, both receptor families are also associated with numerous human diseases. Reciprocal crosstalk between AHR and ERs is proposed to both positively and negatively impact human health. ERs are the most important targets in the treatment of breast cancer. The AHR, which is activated by many environmental pollutants, natural/dietary compounds, and endogenous substances, is a negative regulator of ER function. The role of ERα in AHR signaling is less clear as it is known to exhibit cell-type and promoter-specific differences. In this chapter, we will highlight the current understanding of AHR and ER crosstalk and toxicity.
Authors:Arno G. Siraki Pages: 39 - 82 Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Arno G. Siraki Aromatic amines (also known as arylamines) form a very important class of xenobiotics. The arylamine substructure is found in pesticides, carcinogens, and drugs. It is therefore unsurprising that arylamine drugs possess varying degrees of toxicity which ultimately depend on dose, exposure, and the particular genetic makeup of the individual. Arylamines have been shown to undergo oxidation reactions to produce reactive metabolites. This chapter will focus on a subset of reactive metabolites which are the arylamine-free radical metabolites. A detailed discussion on how these free radical metabolites form is presented, and association between the latter and toxicity reactions are discussed. Particular emphasis is devoted to the subject of arylamine-induced blood dyscrasias and recent advances as well as future prospects in this area.
Authors:Sushmita Sen; Jeffrey M. Field Pages: 83 - 127 Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Sushmita Sen, Jeffrey M. Field Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, so widespread that it is impossible for anyone to avoid exposure to them. They are the products of partial combustion, and exposure comes from the fossil fuels that we use to drive our cars, cook our food, warm our home, and fuel our industry. Other exposure comes from tobacco smoke and oil spills. PAHs are responsible for more cancers, primarily lung cancers, than any other carcinogen. The most studied PAHs are unsubstituted multi-ring structures. These compounds are not DNA reactive, and must be modified to become carcinogenic. Metabolic pathways modify PAH during the detoxification process. Three pathways have been extensively documented: the diol-epoxide pathway, the radical cation pathway, and the o-quinone pathway. Some PAHs are generated during combustion in oxygenated forms, usually as quinones. Quinones also form as PAHs are exposed to sunlight, for example, in an oil spill. These metabolic products damage DNA through distinct mechanisms: diol epoxides form bulky adducts with DNA, radical cations form depurinating adducts and quinones undergo futile redox cycling to generate reactive oxygen. Here, we discuss the evidence for these pathways in PAH carcinogenesis.
Authors:Umeo Takahama; Toshihiro Ansai; Sachiko Hirota Pages: 129 - 177 Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Umeo Takahama, Toshihiro Ansai, Sachiko Hirota Salivary nitrate derived from foods is reduced to nitrite and nitric oxide (NO•) by oral bacteria. NO• is transformed into NO2 •, N2O3, and ONOOH by chemical reactions, and nitrite is oxidized to NO2 • by salivary peroxidase. The formation of reactive nitrogen oxides becomes faster with the decrease in pH of dental plaque from 7 to 5. Reactive nitrogen oxides formed in acidified plaque can activate leukocytes through oxidation, nitration, and nitrosation of free and bacterial proteins in plaque and the gingival crevice. O2 •− and NO• produced by activated leukocytes can contribute to stresses to the gingival tissues. This chapter deals with mechanisms of production of reactive nitrogen oxides in the oral cavity, especially, acidified plaque. Since salivary nitrite is transported to the stomach, this chapter also deals with reactions of salivary nitrite in the stomach.
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