The greater reactivity of estradiol-3,4-quinone vs estradiol-2,3-quinone with DNA in the formation of depurinating adducts: implications for tumor-initiating activity

Chem Res Toxicol. 2006 Jan;19(1):164-72. doi: 10.1021/tx050229y.


Strong evidence supports the idea that specific metabolites of estrogens, mainly catechol estrogen-3,4-quinones, can react with DNA to become endogenous initiators of breast, prostate, and other human cancers. Oxidation of the catechol estrogen metabolites 4-hydroxyestradiol (4-OHE2) and 2-OHE2 leads to the quinones, estradiol-3,4-quinone (E2-3,4-Q) and estradiol-2,3-quinone (E2-2,3-Q), respectively. The reaction of E2-3,4-Q with DNA affords predominantly the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua, whereas the reaction of E2-2,3-Q with DNA yields the newly synthesized depurinating adduct 2-OHE2-6-N3Ade. The N3Ade adducts are lost from DNA by rapid depurination, while the N7Gua adduct is lost from DNA with a half-life of approximately 3 h at 37 degrees C. To compare the relative reactivity of E2-3,4-Q and E2-2,3-Q, the compounds were reacted individually with DNA for 0.5-20 h at 37 degrees C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37 degrees C. Depurinating and stable adducts were analyzed. In similar experiments, the relative reactivity of 4-OHE2 and 2-OHE2 with DNA was determined after activation by lactoperoxidase, tyrosinase, prostaglandin H synthase (PHS), or 3-methylcholanthrene-induced rat liver microsomes. Starting with the quinones, the levels of depurinating adducts formed from E2-3,4-Q were much higher than that of the depurinating adduct from E2-2,3-Q. Similar results were obtained with lactoperoxidase or tyrosinase-catalyzed oxidation of 4-OHE2 and 2-OHE2, whereas with activation by PHS or microsomes, a relatively higher amount of the depurinating adduct from E2-2,3-Q was detected. These results demonstrate that the E2-3,4-Q is much more reactive with DNA than E2-2,3-Q. The relative reactivities of E2-3,4-Q and E2-2,3-Q to form depurinating adducts correlate with the carcinogenicity, mutagenicity, and cell-transforming activity of their precursors, the catechol estrogens 4-OHE2 and 2-OHE2. This is essential information for understanding the cancer risk posed by oxidation of the two catechol estrogens.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / chemistry
  • Carcinogens / chemistry*
  • DNA / chemistry*
  • DNA Adducts / analysis
  • DNA Adducts / chemical synthesis*
  • Deoxyadenosines / chemistry
  • Estradiol / analogs & derivatives*
  • Estradiol / chemistry
  • Estrogens, Catechol / chemistry
  • Guanosine / chemistry
  • In Vitro Techniques
  • Lactoperoxidase / chemistry
  • Monophenol Monooxygenase / chemistry
  • Mutagens / chemistry*
  • Oxidation-Reduction
  • Time Factors


  • Carcinogens
  • DNA Adducts
  • Deoxyadenosines
  • Estrogens, Catechol
  • Mutagens
  • estradiol-3,4-quinone
  • Guanosine
  • estradiol-2,3-O-quinone
  • Estradiol
  • DNA
  • calf thymus DNA
  • 2-hydroxyestradiol
  • 4-hydroxyestradiol
  • Lactoperoxidase
  • Monophenol Monooxygenase
  • Adenine