INHIBITION INVIVO OF THE FORMATION OF ADDUCTS BETWEEN METABOLITES OF BENZO(A)PYRENE AND DNA BY ARYL-HYDROCARBON HYDROXYLASE INDUCERS

Abstract

The lungs of A/HeJ mice are susceptible to benzo(a)pyrene (BP)-induced neoplasia; the livers are resistant. Following p.o. [oral] administration of a carcinogenic dose of [3H]BP, radioactivity was associated with the DNA of both lung and liver. Analysis of the deoxyribonucleosides by high-pressure liquid chromatography showed that the major adduct in both tissues was the (.+-.)-7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEI)-deoxyguanosine adduct. The (.+-.)-7.beta.,8.alpha.-dihydroxy-9.beta.,10.beta.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEII)-deoxyguanosine adduct was 9 to 15% of the BPDEI adduct in both lung and liver. Although total DNA-associated radioactivity was aproximtely 12-fold higher in liver than in lung, the specific activities of the BP diol-epoxide adducts were approximately the same in these organs. Treatment of animals with .beta.-naphthoflavone (.beta.NF), an inhibitor of pulmonary adenoma formation, markedly decreased the amount of the BDPEI and BPDEII adducts in the lung and the liver. The decrease in the lung correlates with the inhibition of tumorigenesis by .beta.NF. The inhibition of total DNA-associated radioactivity was significantly less than the BP diol-epoxide adducts. .beta.NF appears to inhibit BP-induced pulmonary neoplasia by reducing the amount of the BPDEI-deoxyguanosine adduct. Other inducers of aryl hydrocarbon hydroxylase were tested for their effect on the formation of BP-deoxyribonucleoside adducts. Both 2,3,7,8-tetrachlorodibenzo-p-dioxin and Aroclor 1254 significantly reduced the amount of the BPDEI adduct in both lung and liver. Both 2,3,7,8-tetrachlorodibenzo-p-dioxin and Aroclor 1254, like .beta.NF, should protect against BP-induced pulmonary neoplasia. The effects of aryl hydrocarbon hydroxylase inducers on the binding of BP to DNA in vivo markedly contrast with their effect in vitro. Treatment of animals with aryl hydrocarbon hydroxylase inducers stimulates the formation of BP diol-epoxide adducts in vitro. The reason for the differences between in vivo results and those predicted from in vitro studies is unclear.