Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

Abstract

Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.

Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

“…These results are in line with recent experimental evidence that demonstrates a selective PXR agonist activity of GA, which is specific for this vitamin E metabolite (21). Consistent biochemical and functional evidence support these findings including the co-crystallization of GA with the LBD of PXR nuclear receptor, thermodynamic data, target engagement and the transcriptional response of different tissues that include gut and liver tissues in which PXR is abundantly expressed and important for its detoxification function (21). The response of intestinal and hepatic PXR to GA treatment is confirmed in the present study and it is described for first time to extend to some areas of the brain (Fig.…”

“…Because the activity of GA appears to be at least in part independent from PPARg activity, another molecular target of this plant metabolite that may sustain ApoE transport and Ab clearance through P-GP or MDR1 up-regulation (25-27, 29), is PXR (15,21). GA was confirmed to be a potent activator of PXR protein expression also in mouse astrocytes (Fig.…”

“…1). Recent evidence in literature also suggested a function of these LCMs (15), and especially of GA (21), as PXR agonists. This nuclear receptor is a central hub of xenobiotic metabolism (22) and its transcriptional role is proposed to control the CYP450-mediated metabolism of vitamin E, possibly by CYP4F2 and CYP3A4 isoenzyme regulation (14,23,24).…”

Diversity of Chromanol and Chromenol Structures and Functions: An Emerging Class of Anti-Inflammatory and Anti-Carcinogenic Agents

“…However, local accumulation of d-T3-13′-COOH in cells or tissues cannot be excluded. d-T3-13′-COOH can be obtained in relatively high amounts and purity from the seeds of Garcinia kola E. Heckel (Bartolini et al, 2019;Wallert et al, 2019), a plant that is used in traditional African ethnomedicine (extensively reviewed in Kluge et al, 2016). This compound can be used as precursor for the semi-synthesis of aand d-LCMs (including a-T-13′-OH, a-T-13′-COOH, d-T-13′-OH, and d-T-13′-COOH) for experimental use in vitro and in mice and is therefore important for vitamin E metabolite research (Maloney and Hecht, 2005;Birringer et al, 2010).…”

“…Further, d-T3-13′-COOH also appeared to be a potent anti-inflammatory (Wallert et al, 2019) and anti-proliferative agent (Mazzini et al, 2009) and has been shown to act as an inhibitor of DNA polymerase b (Maloney and Hecht, 2005), indicating that d-T3-13′-COOH may disturb base excision repair in tumor cells. A recent preprint of Bartolini et al described d-T3-13′-COOH as a potent agonist of PXR, which is known to be involved in inflammatory processes (Bartolini et al, 2019).…”