P-QUINONE METHIDES ARE THE MAJOR DECOMPOSITION PRODUCTS OF CATECHOL ESTROGEN O-QUINONES

The mechanism of catechol estrogen-induced carcinogenesis could involv e alkylation of critical cellular macromolecules by electrophilic quin oids, The o-quinones formed from peroxidase/P450-catalyzed oxidation o f catechol estrogens have previously been implicated as the ultimate c arcinogens, In the present study, we have shown that additional reacti ve intermediates can be produced from isomerization of the catechol es trogen o-quinones to highly electrophilic p-quinone methides (QMs). Th e o-quinones of the catechol estrogens were incubated at 37 degrees C (pH 7.4) in the absence of GSH. Aliquots were removed at various times and combined with GSH, The GSH adducts were isolated and characterize d by H-1-NMR, UV, and electrospray mass spectrometry, The o-quinone of 2-hydroxyestrone isomerized to two QMs; a QM stabilized by one alkyl substituent in the B ring, 2-OHE-QM1 3-hydroxy-1-(10),3(4),5(6)-oestra trien-2,17-dione) and one having two alkyl substituents on the methyle ne group in the C ring, 2-OHE-QM2 2-hydroxy-1(2),4(5),9(10)-oestratrie n-3,17-dione), Only one QM was observed from the o-quinone of 4-hydrox yestrone, 4-OHE-QM2 (4-hydroxy-1(2),4(5),9(10)-oestratrien-3,17-dione) which is analogous to the C ring analog (2-OHE-QM2) from the o-quinon e of 2-hydroxyestrone, The GSH adduct of 4-OHE-QM2 decomposed at pH 7. 4 to give 9(11)-dehydro-4-hydroxyestrone as the major product, Finally , the disappearance of the estrogen o-quinone GSH adducts correlated w ith the formation of the GSH conjugates of the QMs. These data suggest that in cells with low levels of GSH, the formation of these potent e lectrophiles represents the major reaction pathway for estrogen o-quin ones, The implications of the o-quinone/QM pathway for the in vivo eff ects of catechol estrogens are not known; however, given the direct li nk between excessive exposure to endogenous estrogens and the enhanced risk of breast cancer, the potential for formation of additional reac tive intermediates needs to be explored.