title: 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.
abstract: 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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zahid
authors.forename: Ekta
authors.initials: E
authors.lastname: Kohli
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saeed
authors.forename: Eleanor
authors.initials: E
authors.lastname: Rogan
authors.forename: Ercole
authors.initials: E
authors.lastname: Cavalieri
mesh_terms: D000225:Adenine / Q000737:chemistry; D002273:Carcinogens / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000032:analysis / Q000138:chemical synthesis*; D003839:Deoxyadenosines / Q000737:chemistry; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D002393:Estrogens, Catechol / Q000737:chemistry; D006151:Guanosine / Q000737:chemistry; D066298:In Vitro Techniques; D007784:Lactoperoxidase / Q000737:chemistry; D014442:Monophenol Monooxygenase / Q000737:chemistry; D009153:Mutagens / Q000737:chemistry*; D010084:Oxidation-Reduction; D013997:Time Factors
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D003839:Deoxyadenosines; D002393:Estrogens, Catechol; D009153:Mutagens; C500988:estradiol-3,4-quinone; D006151:Guanosine; C049872:estradiol-2,3-O-quinone; D004958:Estradiol; D004247:DNA; C427203:calf thymus DNA; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D007784:Lactoperoxidase; D014442:Monophenol Monooxygenase; D000225:Adenine