Abstract
Membrane-associated progesterone receptors (MAPR) are a group of four rather small, partially homologous proteins, which share a similar non-covalent heme-binding domain that is related to cytochrome b5, a well-known functional interaction partner of microsomal cytochrome P450 (CYP) monooxygenase systems. Apart from their structural similarities the four proteins progesterone membrane component 1 (PGRMC1, also referred to as IZA, sigma-2 receptor, Dap1), PGRMC2, neudesin (NENF) and neuferricin (CYB5D2) display surprisingly divergent and multifunctional physiological properties related to cholesterol/steroid biosynthesis, drug metabolism and response, iron homeostasis, heme trafficking, energy metabolism, autophagy, apoptosis, cell cycle regulation, cell migration, neural functions, and tumorigenesis and cancer progression. The purpose of this mini-review is to briefly summarize the structural and functional properties of MAPRs with particular focus on their interactions with the CYP system. For PGRMC1, originally identified as a non-canonical progesterone-binding protein that mediates some immediate non-genomic actions of progesterone, available evidence indicates mainly activating interactions with steroidogenic CYPs including CYP11A1, CYP21A2, CYP17, CYP19, CYP51A1, and CYP61A1, while interactions with drug metabolizing CYPs including CYP2C2, CYP2C8, CYP2C9, CYP2E1, and CYP3A4 were either ineffective or slightly inhibitory. For the other MAPRs the evidence is so far less conclusive. We also point out that experimental limitations question some of the previous conclusions. Use of appropriate model systems should help to further clarify the true impact of these proteins on CYP-mediated metabolic pathways.
Highlights
Inter- and intraindividual variability in the expression and activity of drug metabolizing enzymes, transporters and their regulators is a major determinant of drug response, both in terms of drug efficacy and adverse events
The multiple monooxygenase functions of microsomal CYP enzymes strictly depend on protein-protein interactions (PPI) with the single microsomal flavoprotein NADPH:cytochrome P450 oxidoreductase (POR) to allow electron transfer from NADPH to the heme iron (Pandey and Fluck, 2013; Kandel and Lampe, 2014)
Since POR is present in the endoplasmic reticulum (ER) at sub-stoichiometric amounts compared to CYP, it has been proposed that their interactions involve transient oligomeric complexes (Backes and Kelley, 2003)
Summary
Inter- and intraindividual variability in the expression and activity of drug metabolizing enzymes, transporters and their regulators is a major determinant of drug response, both in terms of drug efficacy and adverse events. Apart from this, MAPRs interact with an increasing number of different proteins and are involved in a wide variety of cellular functions including cholesterol and steroid homeostasis, cell cycle regulation, cell migration, neurogenesis, autophagy, heme homeostasis and more that are only briefly mentioned but not the focus of this review Readers interested in these aspects are referred to excellent reviews by others (Losel et al, 2008; Ahmed et al, 2012; Kimura et al, 2012; Neubauer et al, 2013; Cahill et al, 2016; Hasegawa et al, 2016). Ectopic CYB5D2 expression inhibited cell proliferation and anchorage-independent colony growth of HeLa cells (Bruce and Rybak, 2014)
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