Mutagenic properties of estrogen quinone-derived DNA adducts in simian kidney cells

作者：Terashima I; Suzuki N; Shibutani S^*

来源：Biochemistry, 2001, 40(1): 166-172.

DOI：10.1021/bi002273c

DNA damage caused by catechol estrogens has been shown to play an etiologic role in tumor formation. Catechol estrogens are reactive to DNA and form several DNA adducts via their quinone forms. To explore the mutagenic properties of 2-hydroxyestrogen-derived DNA adducts in mammalian cells, N-2-(2-hydroxyestrogen-6-yl)-2 ' -deoxyguanosine and N-6-(2-hydroxyestrogen-6-yl)-2 ' -deoxyaden adducts induced by quinones of 2-hydroxyestrone, 2-hydroxyestradiol, or 2-hydroxyestriol were incorporated site-specifically into the oligodeoxynucleotides (5 ' TCCTCCTC (X) under bar CCTCTC, where X is dG, dA, 2-OHEN2-dG, or 2-OHE-N-6-dA). The modified oligodeoxynucleotides were inserted into single-stranded phagemid vectors followed by transfection into simian kidney (COS-7) cells. Preferential incorporation of dCMP, the correct base, was observed opposite all 2-OHE-N-2-dG adducts. Only targeted G --> T transversions were detected; the highest mutation frequency (18.2%) was observed opposite the 2-OHE2-N-2-dG adduct, followed by 2-OHE1-N-2-dG (4.4%) and 2-OHE3-N-2-dC (1.3%). When 2-OHE-N6-dA adducts were used, preferential incorporation of dTMP, the correct base, was observed. Targeted mutations representing A --> T transversions were detected, accompanied by small numbers of A --> G transitions. The highest mutation frequencies were observed with 2-OHE1-N-6-dA and 2-OHE3-N-6-dA (14.5 and 14.1%, respectively), while 2-OHE2-N-6-dA exhibited a mutation frequency of only 6.0%. No mutations were detected with vectors containing unmodified oligodeoxynucleotides. Thus, 2-OHE quinone-derived DNA adducts are mutagenic, generating primarily G --> T and A --> T mutations in mammalian cells. The mutational frequency varied depending on the nature of the 2-OHE moiety.

• 出版日期2001-1-9