S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling

Expert Opin Drug Metab Toxicol. 2012 Mar;8(3):361-70. doi: 10.1517/17425255.2012.658367. Epub 2012 Feb 1.

Abstract

Introduction: S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome-related protein that binds directly to heme and various pharmacological compounds. S2R(Pgrmc1) also associates with cytochrome P450 proteins, the EGFR receptor tyrosine kinase and the RNA-binding protein PAIR-BP1. S2R(Pgrmc1) is induced in multiple types of cancer, where it regulates tumor growth and is implicated in progesterone signaling. S2R(Pgrmc1) also increases cholesterol synthesis in non-cancerous cells and may have a role in modulating drug metabolizing P450 proteins.

Areas covered: This review covers the independent identification of S2R and Pgrmc1 and their induction in cancers, as well as the role of S2R(Pgrmc1) in increasing cholesterol metabolism and P450 activity. This article was formed through a PubMed literature search using, but not limited to, the terms sigma-2 receptor, Pgrmc1, Dap1, cholesterol and aromatase.

Expert opinion: Multiple laboratories have shown that S2R(Pgrmc1) associates with various P450 proteins and increases cholesterol synthesis via Cyp51. However, the lipogenic role of S2R(Pgrmc1) is tissue-specific. Furthermore, the role of S2R(Pgrmc1) in regulating P450 proteins other than Cyp51 appears to be highly selective, with modest inhibitory activity for Cyp3A4 in vitro and a complex regulatory pattern for Cyp21. Cyp19/aromatase is a therapeutic target in breast cancer, and S2R(Pgrmc1) activated Cyp19 significantly in vitro but modestly in biochemical assays. In summary, S2R(Pgrmc1) is a promising therapeutic target for cancer and possibly cholesterol synthesis but research to date has not identified a major role in P450-mediated drug metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biotransformation
  • Cholesterol / metabolism*
  • Cloning, Molecular
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochromes b5 / metabolism*
  • Dyslipidemias / drug therapy
  • Dyslipidemias / metabolism
  • Hormones / metabolism*
  • Humans
  • Membrane Proteins / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Progesterone / metabolism
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*
  • Receptors, sigma / drug effects
  • Receptors, sigma / metabolism*
  • Signal Transduction* / drug effects

Substances

  • Hormones
  • Membrane Proteins
  • PGRMC1 protein, human
  • Receptors, Progesterone
  • Receptors, sigma
  • sigma-2 receptor
  • Progesterone
  • Cytochromes b5
  • Cytochrome P-450 Enzyme System
  • Cholesterol