Phenolic genotoxicity

Levels of Significant Exposure to Phenol—Inhalation 2-2 Levels of Significant Exposure to Phenol—Oral 2-3 Levels of Significant Exposure to Phenol - Dermal 2-4 Genotoxicity of Phenol In Vivo... 

No studies were located regarding genotoxic effects in humans following oral exposure to phenol. 

In pregnant female mice given 265 mg/kg phenol by gavage on day 13 of gestation, Ciranni et al. (1988) found no evidence of genotoxicity, as measured by an increase in micronuclei in maternal bone marrow or fetal liver. 

It has been suggested that phenol exposure results in cardiac effects because it blocks the cardiac sodium channel subtype, with little effect on sodium channels in skeletal muscle (Zamponi et al. 1994). Phenol does not appear to be carcinogenic following oral exposure (NCI 1980), although the chemical combinations that result from benzene and phenol metabolism may contain compounds that do initiate or promote cancer. Metabolites such as hydroquinone and catechol have been demonstrated to be genotoxic and clastogenic. 

Barale R, Marrazzini A, Betti C, et al. 1990. Genotoxicity of two metabolites of benzene Phenol and hydroquinone show strong synergistic effects in vivo. Mutat Res 244 15-20. 

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. 

Marrazzini, A., Chelotti, L., Barrai, I., Loprieno, N. Barale, R. (1994a) In vivo genotoxic interactions among three phenolic benzene metabolites. Mutat. Res., 341, 29-46... 

DNA damage in the presence of cytochrome P450s (CYPs) and Cu(II) in vitro or in cells [Yoshino et al., 2004 Ahsan et al., 1999]. At higher concentrations curcumin exhibited genotoxicity and cytotoxicity in different systems [Cao et al., 2007]. At last, in vivo intervention trials using typical antioxidants such as ascorbate or carotenes yielded mostly disappointing results in terms of protection against oxidation-related diseases, sometime even increased the incidences of diseases [Stevenson and Hurst, 2007 Dinkova-Kostova and Talalay, 2008]. Obviously, the direct antioxidant capacity of plant phenolic compounds cannot explain their cytoprotective activities. 

Recent applications of CPSA descriptors include QSAR investigations of the genotoxicity of thiophene derivatives (Mosier et al., 2003) as well as of secondary and aromatic amines (Mattioni et al., 2003) and a study to classify phenols with respect to toxic modes of action (Aptula et al., 2003). A somewhat different route has been explored with the concept of dynamic molecular surface areas (Lipkowitz et al., 1989) that represent Boltzmann-weighted means of surface areas of different conformations within a preset energy window (e.g., within an excess of 10.5 kJ/mol above the lowest energy found for the particular molecule). Following this strategy, so-called dynamic polar... 

A proposed metabolic scheme for the metabolism ofthe nonalternant PAH, benzo[b]fluoranthene is presented in Figure 2-4. Nonalternant PAHs, in contrast to several alternant PAHs, do not appear to exert their genotoxic effect primarily through the metabolic formation of simple dihydrodiol epoxides. In the case of benzo[b]fluoranthene, there is evidence to suggest that metabolism to the dihydrodiol precursor to its bay-region dihydrodiol does occur. Rather than this metabolite being converted to its dihydrodiol epoxide however, it appears to be extensively converted to its 5- hydroxy derivative. It is the further metabolism of this phenolic dihydrodiol to 5,9, 10-trihydro... 

Rosenkranz, H. S. Klopman, G. Ohshima, H. Bartsch, H. Structural basis of the genotoxicity of nitro-satable phenols and derivatives present in smoked food products. Mutat. Res. 1990, 230, 9-27. 

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