p-Quinone methides are the major decomposition products of catechol estrogen o-quinones.
The mechanism of catechol estrogen-induced carcinogenesis could involve alkylation of critical cellular macromolecules by electrophilic quinoids. The o-quinones formed from peroxidase/P450-catalyzed oxidation of catechol estrogens have previously been implicated as the ultimate carcinogens. In the present study, we have shown that additional reactive intermediates can be produced from isomerization of the catechol estrogen o-quinones to highly electrophilic p-quinone methides (QMs). The 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 characterized by 1H-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)-oestratrien-2,17-dione) and one having two alkyl substituents on the methylene group in the C ring, 2-OHE-QM2 (2-hydroxy-1(2),4(5),9(10)-oestratrien-3,17-dione). Only one QM was observed from the o-quinone of 4-hydroxyestrone, 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-quinone 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 with 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 electrophiles represents the major reaction pathway for estrogen o-quinones. The implications of the o-quinone/QM pathway for the in vivo effects of catechol estrogens are not known; however, given the direct link between excessive exposure to endogenous estrogens and the enhanced risk of breast cancer, the potential for formation of additional reactive intermediates needs to be explored.
Bolton
J L
JL
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612-7231, USA.
Shen
L
L
D002393:Estrogens, Catechol / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism*
D002393:Estrogens, Catechol; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; C068040:quinone methide; D005978:Glutathione