Radical cations in aromatic hydrocarbon carcinogenesis

Area of Science:

• Biochemistry
• Chemical Biology
• Environmental Health

Background:

• Carcinogens, such as polycyclic aromatic hydrocarbons (PAH), necessitate metabolic activation to form electrophilic species.
• These reactive species covalently bind to cellular macromolecules, initiating the cancer process.
• Metabolic activation of PAH involves pathways like one-electron oxidation and monooxygenation.

Purpose of the Study:

• To investigate the significant role of one-electron oxidation in the metabolic activation of PAH.
• To explore the chemical characteristics of PAH that facilitate this activation pathway.
• To present evidence supporting one-electron oxidation's role in PAH-induced cancer initiation.

Main Methods:

• Analysis of radical cation chemistry in potent carcinogenic PAH.
• Evaluation of ionization potential and charge localization in PAH intermediates.
• Examination of catalytic roles of cytochrome P-450 and mammalian peroxidases in one-electron oxidation.
• Assessment of chemical, biochemical, and biological evidence linking PAH activation to DNA binding.

Main Results:

• Potent carcinogenic PAH exhibit low ionization potentials, enabling facile one-electron removal.
• PAH radical cations show specific and efficient reactivity toward nucleophiles due to charge localization.
• Cytochrome P-450 and mammalian peroxidases catalyze the one-electron oxidation of PAH.
• This mechanism is implicated in the binding of activated PAH to DNA.

Conclusions:

• One-electron oxidation is a crucial pathway for the metabolic activation of carcinogenic PAH.
• The chemical properties of PAH, specifically their ionization potential and radical cation stability, favor this activation route.
• Evidence supports the role of one-electron oxidation in PAH-mediated DNA binding and subsequent cancer initiation.