Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases

ABSTRACT

Introduction: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3ʹ-phosphoadenosine-5ʹ-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury.

Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases.

Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the physiological and pathophysiological effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.

KEYWORDS:

• Estrogen sulfotransferase
• estrogen
• estrogenic drugs
• diseases
• metabolism
• phase II enzymes

Article highlights

• Estrogen sulfotransferase (SULT1E1, also previously known as EST) is a phase II cytosolic enzyme that sulfoconjugates and deactivates estrogens.

• Both endogenous and synthetic estrogens, such as those used as hormone replacement therapies (HRTs) and oral contraceptives, can be metabolized by SULT1E1. Meanwhile, some selective estrogen receptor modulators (SERMs) metabolites and environmental pollutants like polychlorinated biphenyls, may act as inhibitors of the enzyme.

• The transcription of SULT1E1 is subjected to regulation by nuclear receptors and disease states.

• Both the disease effect on SULT1E1 and the SULT1E1 effect on diseases can be tissue-specific and/or sex-specific.

• Although the enzyme was initially implicated in reproduction, several studies conducted in rodents indicate SULT1E1 has crucial roles in non-gonadal organs and possibly has substrates other than the estrogens.

This box summarizes key points contained in the article.

Acknowledgments

The original research of ours described in this article was supported in part by National Institutes of Health (NIH) grant ES023438 and DK083952. W Xie was supported in part by the Joseph Koslow Endowed Chair Professorship from the University of Pittsburgh School of Pharmacy. M Huang was supported in part by the Chinese Ministry of Education 111 Project Grant No. B16047.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.