The Potent Phytoestrogen 8-Prenylnaringenin: A Friend or a Foe?

Abstract

8-prenylnaringenin (8-PN) is a prenylated flavonoid, occurring, in particular, in hop, but also in other plants. It has proven to be one of the most potent phytoestrogens in vitro known to date, and in the past 20 years, research has unveiled new effects triggered by it in biological systems. These findings have aroused the hopes, expectations, and enthusiasm of a "wonder-drug" for a host of human diseases. However, the majority of 8-PN effects require such high concentrations that they cannot be reached by normal dietary exposure, only pharmacologically; thus, adverse impacts may also emerge. Here, we provide a comprehensive and up-to-date review on this fascinating compound, with special reference to the range of beneficial and untoward health consequences that may ensue from exposure to it.

Keywords: beer; flavonoids; isoxanthohumol; naringenin; natural compounds; phytoestrogens; xanthohumol.

Figure 1

Structural formulae of prenylated flavonoids (with the most important compounds for this review in bold). XN can isomerize to IX, and desmethyl-XN to a racemic mixture of 6-PN and 8-PN. IX, in turn, may be metabolized to a variable degree to 8-PN (see text for details). The asterisk indicates the chiral center in 8-PN.

Figure 2

Signaling cascades mediated by 8-PN in tissues and cells (BioRender.com, license purchased). First panel: 8-PN affected steroidogenesis through cAMP-dependent pathway in primary culture of porcine Leydig cells [153]. Second panel: in mouse skeletal muscle, 8-PN stimulated the PI3K/Akt signaling pathway at AS160, which triggers GLUT4 translocation to plasma membrane [106]. Third panel: 8-PN at physiological concentrations activated the PI3K/Akt/P70S6K1 pathway in mouse myotubes and accelerated muscle recovery from disuse atrophy [172]. Fourth panel: In mice, 8-PN activated AMPK, which plays a pivotal role in lipid and glucose metabolism in muscle and liver [106]. Fifth panel: 8-PN is a potential ligand for the human farnesoid X receptor (FXR), based on collective findings from fluorescence titration, molecular docking studies and hydrogen deuterium exchange mass spectrometry [114]. Sixth panel: 8-PN directly activated the inhibitory NO/cGMP/PKG/VASP pathway in human platelets [170]. Seventh panel: 8-PN rapidly activated ERK1/2 MAP kinase in MCF-7 cells [75].