Genotoxicity of combined exposure to polycyclic aromatic hydrocarbons and UVA--a mechanistic study.
Solar UV radiation and benzo[a]pyrene (BaP) are two carcinogenic agents. When combined, their deleterious properties are synergistic. In order to get insights into the underlying processes, we carried out a mechanistic study within isolated DNA photosensitized to UVA radiation by either BaP, its diol epoxide metabolite (BPDE) or the tetraol arising from the hydrolysis of this last molecule. Measurement of the level of the oxidized base 8-oxo-7,8-dihydroguanine revealed that BaP is a poor sensitizer while BPDE and tetraol are more potent ones. None of these compounds was found to photosensitize formation of cyclobutane pyrimidine dimers through triplet energy transfer. On the basis of the distribution of oxidized DNA bases, we could show that photosensitization of DNA by BPDE involves electron abstraction (Type I) while tetraol acts mainly through singlet oxygen production (Type II). Under our experimental conditions, Type I was the major photosensitization process, which shows the lack of involvement of tetraol in the observed photo-oxidation reaction. Finally, we could show that the adducts, resulting from the alkylation of DNA by BPDE, are very potent sensitizers. Indeed, they are located in the close vicinity of the double helix and thus perfectly placed to induce oxidation reactions.
Douki
Thierry
T
Laboratoire "Lésions des Acides Nucléiques," Service de Chimie Inorganique et Biologique UMR-E 3 CEA-UJF, CEA/DSM/INaC, CEA-Grenoble, Grenoble, France. thierry.douki@cea.fr
Ksoury
Zakaria
Z
Marie
Caroline
C
Favier
Alain
A
Ravanat
Jean-Luc
JL
Maitre
Anne
A
D004247:DNA / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D004249:DNA Damage; D009152:Mutagenicity Tests; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000528:radiation effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology* / Q000528:radiation effects; D013997:Time Factors; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
D017319:Photosensitizing Agents; D011084:Polycyclic Aromatic Hydrocarbons; D014867:Water; D004247:DNA