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 aromatichydrocarbon, is the most potent carcinogen ever tested in mouse skin andrat mammary gland. In this study, DB[a,l]P was examined for DNA adduction,tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA instrain A/J mouse lung. Groups of mice received a single i.p. injection of0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment,DNA adducts were measured at times between 1 and 28 days, while tumors werecounted at 250 days and analyzed for the occurrence of point mutations incodons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lunginduced six major and four minor DNA adducts. Maximal levels of adductionoccurred between 5 and 10 days after injection followed by a gradualdecrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti-and syn-11,12- dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and bothdeoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealedby cochromatography. The major adduct was identified as a product of thereaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P inducedsignificant numbers of lung adenomas in a dose- dependent manner, with thehighest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. Intricaprylin-treated control animals, there were 0.67 adenomas/mouse. Basedon the administered dose, DB[a,l]P was more active than other environmentalcarcinogens including benzo[a]pyrene. As a function of time-integrated DNAadduct levels, DB[a,l]P induced lung adenomas with about the same potencyas other PAHs, suggesting that the adducts formed by DB[a,l]P are similarin carcinogenic potency to other PAHs in the strain A/J mouse lung model.Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumorsrevealed the predominant mutations to be G-->T transversions in thefirst base of codon 12, A-->G transitions in the second base of codon12, and A-->T transversions in the second or third base of codon 61,concordant with the DNA adduct profile.