The formation of benzo[a]pyrene—deoxyribonucleoside adducts in vivo and in vitro

Abstract

The formation of DNA-bound products from benzo[a]pyrene was studied using metabolic activation systems of widely differing cellular and structural integrity. The nature of the benzo[a]pyrene-metabolite—deoxyribonucleoside adducts formed was markedly dependent on the nature of the activation system used. Systems where cellular integrity is preserved, namely mouse skin in vivo and rat liver hepatocytes and lung explants in vitro , when treated with benzo[a]pyrene, formed deoxyribonucleoside adducts of which the major one co-chromatographed with a bay-region diol epoxide—deoxyguanosine adduct, 10β-(deoxyguanosin-N ² -yl)-7β,8α,9α-trihydroxy-7,8,9,10-tetrahydrobenzo-[a]pyrene. In striking contrast, the use of activating systems with disrupted cellular integrity such as rat liver, rat lung and mouse skin microsomal fractions, in the presence of benzo[a]pyrene and exogenous DNA, resulted in the formation of deoxyribonucleoside adducts derived predominantly from either a further metabolite of 9-hydroxybenzo[a]pyrene or (±)benzo[a]pyrene-4, 5-epoxide. The consequences of such results are important when considering the widespread use of subcellular fractions such as microsomes as metabolic activating systems for short-term mutagenicity and carcinogenicity tests.