Genotoxicity reaction products

Sasaki, J. C., J. Arey, D. A. Eastmond, K K Parks, and A. J. Grosovsky, Genotoxicity Induced in Human Lymphoblasts by Atmospheric Reaction Products of Naphthalene and Phenan-threne, Mutat. Res., 393, 23-35 (1997b). 

Victorin, K., Busk, L., Cederberg, H. Magnusson, J. (1990) Genotoxic activity of 1,3-butadiene and nitrogen dioxide and their photochemical reaction products in Drosophila and in mouse bone marrow micronucleus assay. Mutat. Res., 228, 203-209... 

Wong, J. W., and Shibamoto,T. (1996). Genotoxicity of the Maillard reaction products. In The Maillard Reaction. Consequences for the Chemical and Life Sciences, Ikan, R., ed., John Wiley Sons, Chichester, UK, pp. 129-159. 

J.W. Wong and T. Shibamoto, Genotoxicity of Maillard reaction products, in The Maillard Reaction Consequences for the Chemical and Life Sciences, R. Ikan (ed), Wiley, Chichester, 1996, 129-159. 

Hydroxyhydroquinone was formed in the thermal degradation of quinic acid (E.62) (Tressl et al., 1978a). It is a possible emetic constituent of coffee. It has been identified in instant coffee by Hiramoto et al. (1998) as the major source of hydrogen peroxide and as such, responsible for the genotoxic activity of coffee, with a higher activity in coffee than the Maillard-reaction products, FuraneolH (1.100), 3,5-dihydroxy 477-pyran-4-one and 5-hydroxy-5,6-dihydromaltol (1.148). 

Ferrand C., Marc F., Fritsch P., Cassand P., de Saint Blanquat G. Genotoxicity study of reaction products of sorbic acid. Journal of Agricultural and Food Chemistry, 48 3605-3610 (2000). 

The PAHs are substances capable of promoting several deleterious effects on organisms. The genotoxicity and mutagenicity of the PAHs can be established by different ways such as the adducts formation originated by the binding of their metabolites, resulted from the biotransformation via CYP with the DNA by the ROS production, from the quinone reaction, product of the PAHs metabolization via CYP, with the O2 among others. 

Phenol-induced oxidative stress mediated by thiol oxidation, antioxidant depletion, and enhanced free radical production plays a key role in the deleterious activities of certain phenols. In this mode of DNA damage, the phenol does not interact with DNA directly and the observed genotoxicity is caused by an indirect mechanism of action induced by ROS. A direct mode of phenol-induced genotoxicity involves covalent DNA adduction derived from electrophilic species of phenols produced by metabolic activation. Oxidative metabolism of phenols can generate quinone intermediates that react covalently with N-1,N of dG to form benzetheno-type adducts. Our laboratory has also recently shown that phenoxyl radicals can participate in direct radical addition reactions with C-8 of dG to form oxygen (O)-adducts. Because the metabolism of phenols can also generate C-adducts at C-8 of dG, a case can be made that phenoxyl radicals display ambident (O vs. C) electrophilicity in DNA adduction. 

In a laboratory environmental chamber study of the gas-phase photooxidation of naphthalene and phenan-threne, Sasaki and co-workers (1997b) found two products, 2-nitronaphthalene and 2-nitrodibenzopyranone (XI), that displayed significant genotoxicity in the MCL-5 human cell assay. This finding emphasized the importance of atmospheric reactions in forming mutagens, since the concentrations of such compounds are relatively high in ambient air compared to those expected for nitroarenes directly emitted from primary combustion sources (see Section F). 

Increased use of liquid chromatography/mass spectrometry (lc/ms) for structural identification and trace analysis has become apparent. Thermo-spray lc/ms has been used to identify by-products in phenyl isocyanate precolumn derivatization reactions Liquid chromatography/thermospray mass spectrometric characterization of chemical adducts of DNA formed during in vitro reaction lias been proposed as an analytical technique to detect and identify those contaminants in aqueous environmental samples which have a propensity to be genotoxic, t.e.. to covalently bond to DNA. 

Fig-1 The final NM-induced toxic effect observed in vitro is the result of multiple processes (1) interaction with proteins (formation of the protein corona, activation/inactivation of enzymes) (2) dissolution and release of toxic ions (3) production of ROS at the NMs surface (4) aggregation/agglomeration (5) diffusion and sedimentation that influence NM transport to the cell layer and the final effective concentration (6) interaction with the cell membrane and membrane receptors (activation/inhibition) (7) cell uptake (including receptor-mediated endocytosis and other uptake mechanisms) (8) interaction with intracellular enzymes (activation/inhibition) (9) production of intracellular ROS (10) activation of transcription factors and (11) binding to nucleic acids and genotoxicity, among others. Processes (1)—(5) are closely interconnected. The resulting effect observed is the result of the composite rate of all these different reactions... 

I The synthesis of often complex chemical structures that bear in themselves sufficient specificity and selectivity for a pharmacological action is only manageable via reactive steps of chemistry. Such reactions often involve or result in electrophilic intermediates, which may possess genotoxic activity. It is a dream of every chemist to create reaction conditions that fully create a product from its educts. This dream can hardly be put into reality. 

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