Identification of a Novel, N7-Deoxyguanosine Adduct as the Major DNA Adduct Formed by a Non-Bay-Region Diol Epoxide of Benzo[a] pyrene with Low Mutagenic Potential

Michael C. MacLeod, K. Leslie Powell, Anne Daylong, Frederick E. Evans, Jack Lay, Paul Chiarelli, Nicholas E. Geacintov, Ernestina Luna, Ronald G. Harvey

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Abstract

A metabolite of benzo [a] pyrene, 9-r, 10-t-dihydroxy-7,8-c-oxy-7,8,9,10-tetrahydrobenzo[a] pyrene (BPDE-III), that is not thought to be involved in carcinogenesis has nevertheless been shown to bind extensively to DNA in vitro. The adducts formed by this non-bay-region diol epoxide in Chinese hamster ovary cells are much less mutagenic than those formed by an isomeric diol epoxide that is carcinogenic. We have isolated and characterized three major adducts formed by in vitro reaction of BPDE-III with DNA. The major adduct, accounting for over half of the total is formed by reaction of BPDE-III with the N7 position of dGuo and is recovered after enzymatic digestion as an N7-Gua adduct. A second major adduct involves the N2 position of dGuo, while the third adduct is tentatively identified as a C8-substituted dGuo. Little or no reaction with deoxyadenosine residues is detected. The N7 adduct is unstable in DNA at 37 °C and is released as the modified base with a half-life of about 24 h. This adduct lability apparently leads to single-strand breaks and alkali-sensitive sites in the DNA and may account in part for some of the biological properties of BPDE-III adducts. This represents the first description of an N7-dGuo adduct that is formed in DNA as the major adduct by a diol epoxide derived from a carcinogenic polycyclic aromatic hydrocarbon.

Original languageEnglish (US)
Pages (from-to)2977-2987
Number of pages11
JournalBiochemistry
Volume33
Issue number10
DOIs
StatePublished - Mar 1 1994

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ASJC Scopus subject areas

  • Biochemistry

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