Numerous studies have suggested that the lifetime dose of unopposed
estrogen is a significant risk factor for breast and
uterine cancer.
Estradiol (E2) plays a putative role as a
tumor promoter through interaction with
estrogen receptors but can also be metabolized to redox active and/or mutagenic semiquinones and
quinones. Similarly, equine
estrogens (components of certain
hormone replacement therapy preparations) are converted to
quinone metabolites. The use of
hormone replacement therapy has also been associated with increased breast and
endometrial cancer risk. Recently, metabolites of certain equine
estrogens have been shown to inhibit human
glutathione S-
transferases (hGSTs). Since E2 and equine
estrogens share similarities in other
biological interactions, we have investigated the inhibitory capacity of endogenously formed E2 metabolites toward various hGSTs. The
quinone metabolite of 2-hydroxy-17-beta-estradiol (2-OH-E2) was synthesized, and inhibition of hGST-mediated biotransformation of model substrates was assessed. Inhibition of purified recombinant hGSTM1-1 and hGSTA1-1 occurred in a concentration-dependent manner with IC50-values of approximately 250 and 350 nM, respectively. hGSTs M2-2, P1-1 and T1-1 were significantly less sensitive to inhibition. Specific
glutathione-conjugates of the
estrogen quinone also potently inhibited hGSTM1-1 and hGSTA1-1. Mass spectrometry data indicate that the inhibition was not mediated via covalent adduction. Although we have demonstrated hGST inhibition via E2 metabolites, our findings indicate that the
isoform specificity and potency of GST inhibition by endogenous E2 metabolites is different than that of equine
estrogen metabolites.