Estradiol metabolites as isoform-specific inhibitors of human glutathione S-transferases

Erika L. Abel, Robert P. Lyon, Theodore K. Bammler, Christophe L M J Verlinde, Serrine Lau, Terrence Monks, David L. Eaton

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Numerous studies have suggested that the lifetime dose of unopposed estrogen is a significant risk factor for breast and uterine cancer. Estradiol (E 2) 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 E 2 and equine estrogens share similarities in other biological interactions, we have investigated the inhibitory capacity of endogenously formed E 2 metabolites toward various hGSTs. The quinone metabolite of 2-hydroxy-17-β-estradiol (2-OH-E 2) 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 IC 50-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 E 2 metabolites, our findings indicate that the isoform specificity and potency of GST inhibition by endogenous E 2 metabolites is different than that of equine estrogen metabolites.

Original languageEnglish (US)
Pages (from-to)21-32
Number of pages12
JournalChemico-Biological Interactions
Volume151
Issue number1
DOIs
StatePublished - Dec 30 2004

Fingerprint

Metabolites
Glutathione Transferase
Estradiol
Protein Isoforms
Estrogens
Horses
Hormone Replacement Therapy
Breast Neoplasms
Quinones
Uterine Neoplasms
Hormones
Endometrial Neoplasms
Biotransformation
Estrogen Receptors
Carcinogens
Oxidation-Reduction
Glutathione
Mass Spectrometry
Mass spectrometry
Substrates

Keywords

  • Biotransformation
  • Conjugation
  • Estradiol
  • Estrogen
  • Glutathione
  • Inhibition
  • Kinetics
  • Transferase

ASJC Scopus subject areas

  • Toxicology

Cite this

Estradiol metabolites as isoform-specific inhibitors of human glutathione S-transferases. / Abel, Erika L.; Lyon, Robert P.; Bammler, Theodore K.; Verlinde, Christophe L M J; Lau, Serrine; Monks, Terrence; Eaton, David L.

In: Chemico-Biological Interactions, Vol. 151, No. 1, 30.12.2004, p. 21-32.

Research output: Contribution to journalArticle

Abel, Erika L. ; Lyon, Robert P. ; Bammler, Theodore K. ; Verlinde, Christophe L M J ; Lau, Serrine ; Monks, Terrence ; Eaton, David L. / Estradiol metabolites as isoform-specific inhibitors of human glutathione S-transferases. In: Chemico-Biological Interactions. 2004 ; Vol. 151, No. 1. pp. 21-32.
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AB - Numerous studies have suggested that the lifetime dose of unopposed estrogen is a significant risk factor for breast and uterine cancer. Estradiol (E 2) 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 E 2 and equine estrogens share similarities in other biological interactions, we have investigated the inhibitory capacity of endogenously formed E 2 metabolites toward various hGSTs. The quinone metabolite of 2-hydroxy-17-β-estradiol (2-OH-E 2) 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 IC 50-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 E 2 metabolites, our findings indicate that the isoform specificity and potency of GST inhibition by endogenous E 2 metabolites is different than that of equine estrogen metabolites.

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