DOSE-RESPONSE RELATIONSHIPS FOR THE BINDING OF BENZO(A)PYRENE METABOLITES TO DNA AND PROTEIN IN LUNG, LIVER, AND FORESTOMACH OF CONTROL AND BUTYLATED HYDROXYANISOLE-TREATED MICE

Abstract

The formation of benzo(a)pyrene (BP) metabolite:DNA adducts in the lung, liver and forestomach of control and butylated hydroxyanisole(BHA)-treated (5 mg/g diet) female A/HeJ mice was examined as a function of BP dose (orally), ranging from 2-1351 .mu.mol/kg. The major identified adduct in each tissue at each dose was the (+)-7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEI):deoxyguanosine adduct. A 7.beta.,8.alpha.-dihydroxy-9.beta.,10.beta.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene:deoxyguanosine adduct, a (-)-BPDEI:deoxyguanosine adduct, and an unidentified adduct were also observed. In the lung and liver of untreated animals, the dose-response curves for BPDEI:DNA adduct levels were sigmoidal. In the forestomach, there was no indication of saturation of DNA binding over the BP dose range examined. The dose-response curves became linear as BP dose approached 0 and thus no threshold dose existed below which binding of BPDEI to DNA did not occur, at least in the lung, liver and forestomach of these mice. In the forestomach, the dose-response curve for BPDEI:DNA adducts in BHA-treated mice, 0.5% of diet for 2 wk, was parallel to the curve for control animals; thus, the inhibition (45%) of adduct formation is independent of BP dose. In contrast, BHA treatment diminished the curvilinear nature of the dose-response curves for BPDE adducts in the lung and liver. The inhibition of BPDEI:DNA adduct formation by BHA in lung and liver was dose dependent. The inhibition of lung (68%) and liver (82%) adduct formation was highest at a BP dose of 270 .mu.mol/kg. As the BP dose approached 0, the inhibition of BPDEI:DNA adduct formation by BHA decreased with BP dose and approached values of .apprx. 40% (lung) and 55% (liver). The dose dependency of the binding of BP metabolites to protein was also examined. BPDEI:DNA adduct concentrations ranged from 2-10% of protein binding concentrations in the liver of untreated animals, from 3-7% in forestomach and from 5-7% in lung. The dose-response curves for protein binding of BP metabolites in the lung and liver from BHA-treated animals were essentially parallel to those in control animals; thus the inhibition of protein binding by BHA treatment had no dose dependency in these organs. No consistent BHA effect was observed on the amount of binding of BP metabolites to forestomach protein.