Peroxidases carcinogenic activators

An alternative mechanism for the esterification of V-OH-AAF is the conversion of 4 to 6, as shown in Fig. 1. 31). The formation of A-acetoxy-AAF can occur by a one-electron oxidation process (Fig. 2). This reaction is catalyzed by various peroxidases (29, 31). In addition to the formation of A-acetoxy-AAF, the potential for the formation of the electrophilic sulfate esters of A-OH-AAF was also studied in vitro. It was demonstrated that 3 -phosphoadenosine-5 -phosphosulfate (PAPS) in the presence of rat liver cytosol catalyzed the formation of the sulfate ester of A-OH-AAF. With the exception of the rabbit, the presence of sulfotransferase activity correlated with the susceptibility of the liver of the various species shown in Table V to the carcinogenic activity of N-OH-AAF. 

Blood is identified in most cases on the basis of the peroxidase-like activity of the heme group of hemoglobin. In the classical blood test, benzidine is oxidized to the quinoidal benzidine blue by hydrogen peroxide in the presence of hemoglobin. Since benzidine and its salts are now considered to be carcinogenic, 3,5,3, 5 -tetranethylbenzidine is used instead. 

The ease of formation of PAH cation-radicals is related to their IP. Above a certain IP, activation by one-electron oxidation becomes unlikely because the removal of one electron by the active forms of P450 or peroxidases is more difficult. A cutoff IP above which one-electron oxidation in not likely to occur was tentatively proposed to be about 7.35 eV (Cavalieri and Rogan 1995). For example, 7,12-dimethylbenz[a]-anthracene has an IP of 7.22 eV and is extremely carcinogenic. Benz[a]anthracene has an IP of 7.54 eV and is very weak in this sense. The active carcinogenicity of dibenz[a,h]anthracene (IP 7.61 eV) is not attributable to the one-electron mechanism. It is worth noting that the one-electron transfer is only one of the operating mechanisms of carcinogenesis. 

Another consequence of these findings is that the same adduct can be formed by a free radical mediated pathway from MAB following a one electron oxidation by peroxides as that formed from methylol or me thimine by a two electron oxidation catalyzed by cytochrome P450. Clearly identification of the GSH adducts of carcinogens in vivo may not distinguish both metabolic activation systems. It is also still not clear whether cytochrome P450 and peroxidases form common intermediates during N-demethylation reactions (22-24). 

Another class of heme proteins containing iron protoporphyrin as the active center includes enzymes such as cytochrome P-450 and horseradish peroxidase (HRP). The former is a monooxygenase enzyme (MW 50,000) that catalyzes hydroxylation reaction of substrates such as drugs, steroids and carcinogens ... 

Other heme compounds are also active biochemically. Cytochrome P-450 catalyzes oxidation reactions in the liver and adrenal cortex, helping to detoxify some substances by adding hydroxyl groups that make the compounds more water-soluble and more susceptible to further reactions. Unfortunately, at times this process has the reverse effect because some relatively safe molecules ai-e converted into potent carcinogens. Peroxidases and catalases are Fe(III)-heme compounds that decompose hydrogen peroxide and organic peroxides. The reactions seem to proceed through Fe(IV) compounds with another unpaired electron on the porphyrin, which becomes a radical cation. Similar intermediates are also known in simpler porphyrin molecules. ... 

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,... 

Melendez-Colon, V. J., Luch, A., Seidel, A., and Baird, W. M. (1999b). Comparison of cytochrome P450- and peroxidase-dependent metabolic activation of the potent carcinogen dibenzo[a,l]pyrene in human cell lines formation of stable DNA adducts and absence of a detectable increase in apurinic... 

Heme peroxidases, their structure, function, mechanism, and involvement in activation of carcinogens 00CCC297. 

Uses reagent in a sensitive staining procedure for the detection of low levels of heme-associated peroxidase activity of cytochrome P-450 on SDS-polyacrylamide or agarose gel non-carcinogenic substitute for benzidine as reagent for the detection of blood and determination of hemoglobin content A... 

PAHs are metabolized by a variety of xenobiotic-metabolizing enzymes (Baird et al., 2005). CYP and epoxide hydrolase eonvert the PAH into PAH-diols and these products are transformed in metabolites, potentially, carcinogenic, by the CYP aetion, forming PAH diol-epoxides or by the Aldo-keto-reductase action, generating PAH o-quinones. PAHs can be also activated by CYP and by peroxidases, forming the reactive cations radicals, which bind, covalently, to DNA. Intermediary products formed are still metabolized by enzymes of phase 11, resulting in metabolites more polars and soluble in water becoming ready to be excreted by the body (Shimada, 2006). 

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