Role of Radical Cations in Aromatic Hydrocarbon Carcinogenesis

Abstract

Carcinogenic activation of polycyclic aromatic hydrocarbons (PAH) involves two main pathways: oneelectron oxidation and monooxygenation. One-electron oxidation produces PAH radical cations, which can react with cellular nucleophiles. Results from biochemical and biological experiments indicate that only PAH with ionization potentials below ca. 7.35 eV can be metabolically activated by one-electron oxidation. In addition, the radical cations of carcinogenic PAH must have relatively high charge localization to react effectively with macromolecules in target cells. Metabolic formation of PAH quinones proceeds through radical cation intermediates. Binding of benzo[a]pyrene (BP) to mouse skin DNA occurs predominantly at C-6, the position of highest charge localization in the BP radical cation, and binding of 6-methylBP to DNA in mouse skin yields a major adduct with the 6-methyl group bound to the 2-amino group of deoxyguanosine. Studies of carcinogenicity by direct application of PAH to rat mammary gland indicate that only PAH with ionization potentials low enough for activation by one-electron oxidation produce tumors in this target tissue. These constitute some of the results which provide evidence for the involvement of one-electron oxidation in PAH carcinogenesis.

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

“…These characteristics are: first, a relatively low ionization potential, which allows the removal of one electron and the formation of a relatively stable radical cation; second, a charge localization in the radical cation that renders this intermediate specifically and efficiently reactive toward nucleophiles; and third, an optimal geometric configuration that allows Cavalieri & Rogan (1985) Nu, Nucleophile; PAH, polycyclic aromatic hydrocarbon the formation of appropriate intercalating radical-cation complexes with DNA, and thus favours the formation of covalent DNA adducts.…”

“…Development of the chemistry of PAH radical cations has provided evidence that these intermediates can play a role in the process of tumour initiation of several potent PAHs (Cavalieri & Rogan, 1985, 1992. Radical cations of unsubstituted and methylsubstituted PAHs have been generated by iodine oxidation (Hanson et al, 1998), manganic acetate oxidation (Cremonesi et al, 1992) and electrochemical oxidation (RamaKrishna et al, 1993a,b), with subsequent binding to nucleophiles.…”

Activities of oxidoreductase enzymes in tissue extracts and sterile root exudates of three crop plants, and some properties of the peroxidase component

“…Formation of Mn$ + can also be initiated by phenoxy and aryloxy radicals that had been formed from phenolic substrates by HRP (Kenten & Mann, 1950), laccase (Archibald & Roy, 1992), or lignin peroxidase (Popp, Kalyanaraman & Kirk, 1990). Mn$ + ions are stabilized by chelating ligands such as organic acids, pyrophosphate, and short-chain polyphosphates, and are potent oxidants of phenolic substrates and synthetic lignins (Cavalieri & Rogan, 1985 ;Archibald & Roy, 1992 ;Wariishi et al, 1992). The formation of Mn$ + from Mn# + by peroxidases and laccases creates oxidants with ionization potentials of up to 7n8 eV (Cavalieri & Rogan, 1985).…”

“…Mn$ + ions are stabilized by chelating ligands such as organic acids, pyrophosphate, and short-chain polyphosphates, and are potent oxidants of phenolic substrates and synthetic lignins (Cavalieri & Rogan, 1985 ;Archibald & Roy, 1992 ;Wariishi et al, 1992). The formation of Mn$ + from Mn# + by peroxidases and laccases creates oxidants with ionization potentials of up to 7n8 eV (Cavalieri & Rogan, 1985). These allow peroxidases (for substrates up to 7n35 eV ; Cavalieri et al, 1983), and laccases (for substrates up to 7n45 eV ; Collins et al, 1996) to participate in lignin degradation in a way which would be impossible for the enzymes alone.…”

High resolution fluorescence studies of metabolic pathways of DNA and oligonucleotide adducts from polycyclic aromatic compounds

“…Under the assumption that DNA-carcinogen adducts lead to Schematic representation of the principal events in chemical carcinogenesis genetic lesions, including mutations, adduct formation is deserving of intense study. The current view of metabolic activation in the initiation process is that there are two major pathways: monooxygenation to yield diol epoxides [23][24][25]27,28,[31][32][33] and one-electron oxidation to produce radical cations [34][35][36]. The nature of these pathways will be discussed in more detail in the next section.…”