Carcinogenesis, Vol 18, 1093-1101, Copyright © 1997 by Oxford University Press
L Shen, E Pisha, Z Huang, JM Pezzuto, E Krol, Z Alam, RB van Breemen and JL Bolton
There is a clear association between excessive exposure to estrogens and
the development of cancer in several tissues including breast and
endometrium. The risk factors for women developing these cancers are all
associated with longer estrogen exposure, as may be facilitated by early
menses, late menopause and long-term estrogen replacement therapy.
Equilenin (1,3,5(10),6,8-estrapentaen-3-ol-17-one) or its 17- hydroxylated
analogs make up 15% of the most widely prescribed estrogen replacement
formulation, Premarin, and yet there is very little information on the
human metabolism of these estrogens. In this study, we synthesized the
catechol metabolite of equilenin, 4- hydroxyequilenin, and examined how
aromatization of the B ring affects the formation and reactivity of the
o-quinone (3,5-cyclohexadien-1,2- dione). 4-Hydroxyequilenin-o-quinone is
much more redox-active and longer-lived than the endogenous catechol
estrone-o-quinones, which suggests that the mechanism(s) of toxicity of the
former could be quite different. Interestingly, the rate of reduction of
the 4- hydroxyequilenin-o-quinone is increased at least 13-fold in the
presence of NAD(P)H:quinone oxidoreductase (DT-diaphorase). Once NADH is
consumed however, the catechol auto-oxidized rapidly to the o- quinone.
NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both
with the purified enzyme and with cytosol from human melanoma cells with
high levels of DT-diaphorase activity. P450 reductase and rat liver
microsomes also catalyzed NADPH consumption and oxygen uptake.
4-Hydroxyestrone-o-quinone was also rapidly reduced by NAD(P)H; however,
this o-quinone does not auto-oxidize and once the o- quinone is reduced the
reaction terminates. Including oxidative enzymes in the incubation
completes the redox couple and 4-hydroxyestrone-o- quinone behaves like
4-hydroxyequilenin-o-quinone. These data suggest that reduction of
estrogen-o-quinones may not result in detoxification. Instead this could
represent a cytotoxic mechanism involving consumption of reducing
equivalents (NADH/NADPH) as well as formation of superoxide and other
reactive oxygen species leading to oxidative stress. Finally, we have
compared the cytotoxicity of 4- hydroxyequilenin with that of the estrone
catechols in human melanoma cells. 4-Hydroxyequilenin is 5-fold more toxic
in these cells compared with 4-hydroxyestrone (ED50 = 7.8 versus 38 microM,
respectively) suggesting that formation of the longer-lived redox-active 4-
hydroxyequilenin-o-quinone was responsible for the cytotoxic differences.
These results substantiate the conclusion that the involvement of quinoids
in catechol estrogen toxicity depends on a combination of the rate of
formation of the o-quinone, the lifetime of the o-quinone, and the
electrophilic/redox reactivity of the quinoids.
ARTICLES
Bioreductive activation of catechol estrogen-ortho-quinones: aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity
Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 60612-7231, USA.
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