Polycyclic metabolic pathway

Nitro polycyclic aromatic hydrocarbons are environmental contaminants which have been detected in airborne particulates, coal fly ash, diesel emission and carbon black photocopier toners. These compounds are metabolized Tn vitro to genotoxic agents through ring oxidation and/or nitroreduction. The details of these metabolic pathways are considered using 4-nitrobiphenyl, 1- and 2-nitronaphthalene, 5-nitro-acenaphthene, 7-nitrobenz[a]anthracene, 6-nitro-chrysene, 1-nitropyrene, 1,3-, 1,6- and 1,8-dinitro-pyrene, and 1-, 3- and 6-nitrobenzo[a] pyrene as examples ... 

Karp, J.M., Rodrigo, K.A., Pei, P., Pavlick, M.D., Andersen, J.D., McTigue, D.J., Fields, H.W. and Mallery, S.R. (2005) Sanguinarine activates polycyclic aromatic hydrocarbon associated metabolic pathways in human oral keratinocytes and tissues. Toxicology Letters, 158, 50-60. 

It is clear that the effects of induction or inhibition of the metabolism will be complex because of the large number of possible metabolic pathways through which benzofalpyrene may be metabolized. For instance, the microsomal enzyme inducer 5,6-benzoflavone inhibits the carcinogenicity of benzofalpyrene in mouse lung and skin, whereas inhibitors such as SKF 525A may increase the tumor production from certain polycyclic hydrocarbons. 

Figure 5.4. Metabolic pathways of polycyclic aromatic hydrocarbon oxidation by white-rot fungi.

Metabolic activation systems—such as microsome-, cell-, and host-mediated assays—have been included in mammalian cell mutagenesis systems. Microsome-mediated assays have been used to detect many chemicals, including nitrosamines, polycyclic hydrocarbons, aflatoxins, and vinyl chloride. Cell-mediated assays seem to be a better indicator of in vivo metabolic pathways. Microsome-mediated assays seem suitable for general screening of chemicals, and cell-mediated assays are more valuable in the assessment of data. 

Polycyclic Aromatic Hydrocarbons Multiple Metabolic Pathways and the DNA Lesions Formed... 

Tobacco smoke contains polycyclic aromatic compounds and other substances, which are potent inducers of the liver enzymes that metabolise quinine. It is not yet clear which cytochrome P450 isoenzymes are affected. Smoking induces CYPIA, but the formation of the major metabolite of quinine, 3-hydroxyquinine, is catalysed by CYP3A, which suggests that other metabolic pathways of quinine are affected by smoking. ... 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Oxidation is intimately linked to the activation of polycyclic aromatic hydrocarbons (PAH) to carcinogens (1-3). Oxidation of PAH in animals and man is enzyme-catalyzed and is a response to the introduction of foreign compounds into the cellular environment. The most intensively studied enzyme of PAH oxidation is cytochrome P-450, which is a mixed-function oxidase that receives its electrons from NADPH via a one or two component electron transport chain (10. Some forms of this enzyme play a major role in systemic metabolism of PAH (4 ). However, there are numerous examples of carcinogens that require metabolic activation, including PAH, that induce cancer in tissues with low mixed-function oxidase activity ( 5). In order to comprehensively evaluate the metabolic activation of PAH, one must consider all cellular pathways for their oxidative activation. 

PGH synthase and the related enzyme lipoxygenase occupy a position at the interface of peroxidase chemistry and free radical chemistry and can clearly trigger metabolic activation by both mechanisms. The peroxidase pathway activates compounds such as diethylstilbestrol and aromatic amines whereas the free radical pathway activates polycyclic hydrocarbons (59). Both pathways require synthesis of hydroperoxide in order to trigger oxidation. 

Figure 5.3. The major pathways in the microbial metabolism of polycyclic aromatic hydrocarbons.

During cooxidation, some substrates are activated to become more toxic than they were originally. In some cases substrate oxidation results in the production of free radicals, which may initiate lipid peroxidation or bind to cellular proteins or DNA. Another activation pathway involves the formation of a peroxyl radical from subsequent metabolism of prostaglandin G2. This reactive molecule can epoxidize many substates including polycyclic aromatic hydrocarbons, generally resulting in increasing toxicity of the respective substrates. 

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