Xenobiotics, initial oxidation

These have already been noted in the context of hydroxyl radical-initiated oxidations, and reference should be made to an extensive review by Worobey (1989) that covers a wider range of abiotic oxidations. Some have attracted interest in the context of the destruction of xenobiotics, and reference has already been made to photochemically induced oxidations. 

These fatty acids play an important role also in the amelioration of autoimmune diseases, such as arthritis, and in the inhibition of the rapid proliferation of cancer cells. However, PUFA in membrane lipids are vulnerable to free radical-initiated oxidation, generated by xenobiotics or normal aerobic cellular metabolism that results in the formation of lipid peroxides [84]. 

In a classical study, it was shown that during bacterial oxidation of benzene to catechol both atoms of oxygen came from 62 (Gibson et al. 1970). This initiated the appreciation of the role of dioxygenases in the degradation of aromatic xenobiotics, and many examples are given in Chapter 8, Parts 1 and 2. 

MnP is the most commonly widespread of the class II peroxidases [72, 73], It catalyzes a PLC -dependent oxidation of Mn2+ to Mn3+. The catalytic cycle is initiated by binding of H2O2 or an organic peroxide to the native ferric enzyme and formation of an iron-peroxide complex the Mn3+ ions finally produced after subsequent electron transfers are stabilized via chelation with organic acids like oxalate, malonate, malate, tartrate or lactate [74], The chelates of Mn3+ with carboxylic acids cause one-electron oxidation of various substrates thus, chelates and carboxylic acids can react with each other to form alkyl radicals, which after several reactions result in the production of other radicals. These final radicals are the source of autocataly tic ally produced peroxides and are used by MnP in the absence of H2O2. The versatile oxidative capacity of MnP is apparently due to the chelated Mn3+ ions, which act as diffusible redox-mediator and attacking, non-specifically, phenolic compounds such as biopolymers, milled wood, humic substances and several xenobiotics [72, 75, 76]. 

Recall from Section 1.9 that some molecules can exist as chiral enantiomers that are mirror images of each other. Although enantiomers may appear to be superficially identical, they may differ markedly in their metabolism and toxic effects. Much of what is known about this aspect of xenobiotics has been learned from studies of the metabolism and effects of pharmaceuticals. For example, one of the two enantiomers that comprise antiepileptic Mesantoin is much more rapidly hydroxylated in the body and eliminated than is the other enantiomer. The human cytochrome P-450 enzyme denoted CYP2D6 is strongly inhibited by quinidine, but is little affected by quinine, an optical isomer of quinidine. Cases are known in which a chiral secondary alcohol is oxidized to an achiral ketone, and then reduced back to the secondary alcohol in the opposite configuration of the initial alcohol. 

Prostaglandin synthetase, peroxidase or lipid peroxidation have been shown to oxidise arylamine xenobiotics to reactive species that bind extensively to DNA. The binding could be an initial event in the toxic or carcinogenic process. Evidence is presented that cation radicals are involved in the formation of the various oxidation products and DNA adduct formation with the carcinogen aminofluorene. Furthermore methylaminoazobenzene (butter yellow) was found to form the same major GSH adduct as is formed in vivo. 

Figure 1. Schematic diagram shows the interaction between iipid constituents, products of iipid oxidation, and xenobiotics, which can initiate or promote chronic disease states (6).

The principal pathway by which unsubstituted and many substituted aromatic hydrocarbons are metabolized in mammals consists of the initial formation of arene oxides, which undergo a variety of enzymatic and nonenzymatic reactions prior to excretion of the resulting more polar, oxidized hydrocarbons via bile or urine. Taken together, these pathways represent an attempt on the part of the animal to detoxify or eliminate such nonpolar xenobiotic substances for which it has no apparent use. Although detoxification is the probable role of the arene oxide pathway, it is equally clear that chemically reactive species mediate this process. Thus, studies over the past several years have either implicated or established arene oxides in a causative role in such adverse biological reactions as cytotoxicity, mutagenesis, and carcinogenesis via covalent interaction of arene oxides with biopolymers,... 

The catalytic role that the cytochrome P-450 monooxygenase system plays in the oxidation of xenobiotics is summarized in the cycle shown in Figure 4-1. - The initial... 

The metabolism of xenobiotics in higher plants has been studied extensively over the last 20 years. In common plant species such as corn, it is frequently possible to predict the conjugation reactions that may be utilized in the initial phases of metabolism of a new xenobiotic. In less commonly studied species, predictions are more uncertain and exotic metabolites sire occaslonaly formed. In those cases where phase I oxidative reactions are likely, it is difficult to predict the course of metabolism because phase I oxidation reactions in plants are frequently very substrate and species specific. Phase I oxidative reactions have a profound effect on ensuing conjugation reactlcxis. The presence of multiple functional groups on a xenobiotic also Increases the uncertainty of the route of metabolism likely to be followed in a particular species. 

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