DIBENZO[A,L]PYRENE-INDUCED DNA ADDUCTION, TUMORIGENICITY, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A J MOUSE LUNG/

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hy drocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduc tion, tumorigenicity, and induction of Ki-ras oncogene mutations in tu mor DNA in strain A/J mouse lung. Groups of mice received a single i.p . injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Fo llowing treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occu rrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days a fter injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and ,14-epoxy-11,12,13,14-te trahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatogr aphy The major adduct was identified as a product of the reaction of a n anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbe rs of lung adenomas in a dose-dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated contr ol animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens in cluding benzo[a]pyrene. As a function of time-integrated DNA adduct le vels, DB[a,l]P induced lung adenomas with about the same potency as ot her PAHs, suggesting that the adducts formed by DB[a,l]P are similar i n carcinogenic potency to other PAHs in the strain A/J mouse lung mode l. Analysis of the Ki-ras mutation spectrum in DB[a,l]P-induced lung t umors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of co don 12, and A-->T transversions in the second or third base of codon 6 1, concordant with the DNA adduct profile.