32P-postlabeling analysis of dibenz[a,j]acridine DNA adducts in mice: preliminary determination of initial genotoxic metabolites and their effect on biomarker levels.
N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. NHA are found in significant amounts in tobacco condensates, synthetic fuels, gasoline engine exhaust, and effluents from the heating of coal. Dibenz[a,j]acridine (DBA) is an example of NHA. The potency of many carcinogenic compounds is related, at least in part, to the efficiency of their biological activation. We undertook studies to determine which initial metabolites of DBA lead to the formation of high levels of carcinogen-DNA adducts in vivo. DBA and its metabolites, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD), and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were applied to the skin of mice. DNA was isolated using enzyme-solvent extraction method. DNA was 32P-postlabeled under conditions of limiting [32P]ATP. In skin, DBA produced two distinct adducts. The same two adducts were seen when DBA-3,4-DHD was applied. In addition the total adduct level elicited by DBA-3,4-DHD was higher than that of parent compound. Two adducts were seen when DBA-5,6DHD was applied, but these were very different from adducts seen with DBA. These results suggested that activation of DBA to DNA-binding compounds in skin includes initial formation of DBA-3,4-DHD. The data support development of biomarkers for the exposure and effect of this compound, and also suggest that specific metabolic susceptibility markers might be able to predict populations at increased risk.
Roh
J
J
Dept. of Preventive Medicine and Public Health, Yonsei University College of Medicine, Seoul, Korea.
Schamer
M
M
Reilman
R
R
Xue
W
W
Warshawsky
D
D
Talaska
G
G
D000166:Acridines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002274:Carcinogens, Environmental / Q000009:adverse effects / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010761:Phosphorus Radioisotopes
D000166:Acridines; D015415:Biomarkers; D002274:Carcinogens, Environmental; D009153:Mutagens; D010761:Phosphorus Radioisotopes; C022289:dibenzacridine; D004247:DNA