Quinone metabolic activation

K. Mizutani, T. Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice. Biol. Pharm. Bull. 1997, 20, 571-573. (c) McCracken, P. G. Bolton, J. L. Thatcher, G. R. J. Covalent modification of proteins and peptides by the quinone methide from 2-rm-butyl-4,6-dimethylphenol selectivity and reactivity with respect to competitive hydration. J. Org. Chem. 1997, 62, 1820-1825. (d) Reed, M. Thompson, D. C. Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di- m-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 1997, 10, 1109-1117. (e) Lewis, M. A. Yoerg, D. G. Bolton, J. L. Thompson, J. Alkylation of 2 -deoxynucleosides and DNA by quinone methides derived from 2,6-di- m-butyl-4-methylphenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

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. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Metodiewa D, Jaiswal AK, Cenas N, Dickancaite E, Segura-Aguilar J. 1999. Quinone may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal products. Free Radic Biol Med 26 107-116. 

Covalent protein adducts of quinones are formed through Michael-type addition reaction with protein sulfhydryl groups or glutathione. Metabolic activation of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al., 1997 Rappaport et al., 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-hromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al., 1998). 

Paracetamol, adriamycin, quinones, nitrosamines, aromatic amines, halothane etc. form free-radical intermediates by metabolic activation in the liver.)... 

In conclusion, although it is fair to say that the mechanism of the antitumor activity of ellipticines and related compounds remains unproved, metabolic activation of an ellipticine to a quinone imine or related species of high elec-... 

Han, X. Liehr, J.G. Microsome-mediated 8-Hydroxylation of guanine bases of dna by steroid estrogens correlation of DNA damage by free radicals with metabolic activation to quinones. Carcinogenesis 1995, 16, 2571-2574. 

Metabolic activation of carcinogens involves many enzymatic systems, known as phase I enzymes. The most important is the cytochrome P450 complex, consisting of several different isoenzymes, which are particularly active in the liver. Other enzymes include peroxidases, quinone reductases, epoxide hydrolases, sulfotrans-ferases, and others. Their variety reflects the diversity of chemical structures of compounds to which an organism is exposed. These may be harmful substances or needed ones, or even those indispensable for its proper functioning. One could argue that the activation of carcinogens is an undesirable side effect of metabolic pathways,... 

Figure 6.3. The metabolic activation of PAH through diol epoxide, radical cation, o-quinone, and arene oxide activation mechanisms.

Figure 6.7. The metabolic activation of fra 5 -B[a]P-7,8-diol to B[a]P-7,8-quinone by AKR and the generation of ROS from Burczynski and Penning (2000).

Kalgutkar, A.S. et al., Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4, Chem. Biol. Interact., 155(1-2), 10, 2005. 

The polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that have been implicated as etiological factors in human chemical carcinogenesis (13, 14). One such PAH that has been studied extensively is benzo[a]-pyrene (G3). The metabolic activation of this compound to various reactive intermediates, including epoxides, phenols, and quinones, is performed by the cytochrome-P450-containing mixed function oxidase (MFO) system. Subsequent metabolic steps may involve the hydration of epoxides to dihydrodiols, mediated... 

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