Formation and Persistence of Benzo(a)pyrene Metabolite-DNA Adducts

Benzo(a)pyrene (BP) and other polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants and are suspected to be carcinogenic in man. The in vivo formation of BP metabolite-DNA adducts has been characterized in a variety of target and nontarget tissues of mice and rabbits. Tissues included were lung, liver, forestomach, colon, kidney, muscle, and brain. The major adduct identified in each tissue was the (+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydro-BP (BPDEI)-deoxyguanosine adduct. A 7β,8α-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydro-BP (BPDEII)-deoxyguanosine adduct, a (-)-BPDEI-deoxyguanosine adduct, and an unidentified adduct were also observed. The adduct levels are unexpectedly similar in all the tissues examined from the same BP-treated animal. For example, the BPDEI-DNA adduct levels in muscle and brain of mice were approximately 50% of those in lung and liver at each oral BP dose used. We have also examined adduct levels formed in vivo in several cell types of lung and liver. Macrophages, type II cells, and Clara cells from lung and hepatocytes and nonpparenchymal cells from liver were isolated from BP-treated rabbits. BPDEI-deoxyguanosine adduct was observed in each cell type and, moreover, the levels were similar in various cell types. These and previous results strongly suggest that DNA in many human tissues is continuously damaged from known exposure of humans to BP and other PAH. Moreover, DNA adducts formed from BP are persistent in lung and brain. The persistence of adducts in cell types that have slow turnover rates could result in significant accumulation of adducts from long-term exposure to low levels of BP. BPDEI-DNA adducts and other bulky adducts are known to inhibit replication and transcription in in vitro systems. Even if environmental exposure to PAH is too low to induce neoplasia, the accumulation of DNA adducts may produce aberrations in transcripts of genetic information in various cells and lead to other toxic effects. Thus, further elucidation of the mechanism by which BP(PAH) metabolites bind to DNA of specific cell types and of the cell-selective repair of the adducts should enhance our understanding of the potential health risk from exposure to this class of environmental pollutants.