Mechanism of metabolic activation and DNA adduct formation by the @entity1 carcinogen XXXX : the defining link to natural estrogens.

@entity1 @entity3276 @entity68513 @entity5 @entity12592 @entity4743 @entity71506 @entity15 @entity4742 @entity11442 @entity19851 @entity15060 @entity6153
@entity4742 ( @entity4743 ) is a @entity1 carcinogen, based on sufficient epidemiological evidence. @entity4743 is mainly metabolized to its @entity6153 , 3'-hydroxyDES (3'-OH-DES), which can further oxidize to DES-3',4'-quinone (DES-3',4'-Q). Similarly to @entity71506 , the reaction of DES-3',4'-Q with DNA would form the depurinating 3'-OH- @entity12592 '-N3Ade and 3'-OH- @entity12592 '-N7Gua adducts. To prove this hypothesis, synthesis of DES-3',4'-Q by oxidation of 3'-OH-DES with @entity19851 was tried; this failed due to instantaneous formation of a spiro-quinone. Oxidation of 3'-OH-DES by lactoperoxidase or @entity11442 in the presence of DNA led to the formation of 3'-OH- @entity12592 '-N3Ade and 3'-OH- @entity12592 '-N7Gua adducts. These adducts were tentatively identified by LC- @entity15 / @entity15 as 3'-OH- @entity12592 '-N3Ade, m/z = 418 [M+H](+), and 3'-OH- @entity12592 '-N7Gua, m/z = 434 [M+H](+). Demonstration of their structures derived from their oxidation by MnO(2) to the @entity4743 @entity3276 adducts and subsequent tautomerization to the @entity68513 (DIES) @entity6153 adducts, which are identical to the standard 3'-OH-DIES-6'-N3Ade, m/z = 416 [M+H](+), and 3'-OH-DIES-6'-N7Gua, m/z = 432 [M+H](+), adducts. The reaction of DIES-3',4'-Q or lactoperoxidase-activated 3'-OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the @entity15060 planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3'-OH-DES suggests that the @entity6153 of @entity4743 intercalates into DNA and is then oxidized to its @entity3276 to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of @entity5 initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol quinones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.
