Metabolic Activation of PAHs

The most widely accepted pathway of PAH activation to yield DNA adducts involves the formation of anti- or syn-diol epoxides in the bay region [12, 13], Their formation is mediated by the sequential reaction of cytochrome P450 and epoxide hydratase, and is best described using the example of B[a]P. 

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At present a variety of studies with PAH, as well as other chemicals, suggest that metabolic activation in target tissues can occur by one-electron oxidation (6,7). The electrophilic intermediate radical cations generated by thTs mechanism can react directly with various cellular nucleophiles. In this paper, we will discuss chemical, biochemical and biological evidence which indicates that one-electron oxidation plays an important role in the metabolic activation of PAH. 

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. 

The reason that one-electron oxidation is suggested as playing a central role in the metabolic activation of PAHs concerns certain features of the cation-radicals that are common to the most potent carcinogens of the family. 

Metabolic activation of PAHs consists of an oxidation of the rings of unsubstituted PAHs. These oxidations are carried out by mixed function oxidases of the liver which contain cytochromes P450 and P448 and require reduced nicotine adenine dinucleotide and oxygen. In this oxidation, an epoxide intermediate is formed which has been shown to have the requisite chemical reactivity to bind covalently with DNA and histones and to serve as the ultimate carcinogenic form of PAH. Administration of 3-MC to rats increased hepatic nuclear proteins and caused a turnover of protein of the endoplasmic reticulum. Studies of " C amino acid incorporation showed that 3-MC causes increased protein synthesis and reduced degradation of protein. 

Varanasi, U., W.M. Baird and T.A. Smolarek. Metabolic activation of PAHs in subcellular fractions and cell cultures from aquatic and terrestrial species. In Metabolism of Polycyclic Aromatic Hydrocarbons in the Aquatic Environment, edited by U. Varanasi, Boca Raton, FL, CRC Press, 1989, Chapter 6. 

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

Scheme 6.3 Metabolic activation of PAHs to radical cations.

It is evident from the previous sections that carcinogenicity (and mutagenicity) are composite properties which are influenced by metabolic activation of PAH to PAHDE and PAHTC and the subsequent binding to cellular macromolecules like DNA. The mutation induction may reflect different isomers of PAHDE s. This in turn may lead to a greater probability of error during repair or replication of sequences containing adducts of the more active diol epoxides. 

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