Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

Abstract

Pregnane X receptor (PXR) is known as a xenosensor, playing a key role in response to xenochemical stimuli. Activation of PXR enhanced expression of various drug-metabolizing enzymes and transporters such as cytochrome P450 3A4 (CYP3A4). During a screening of a natural compounds library for novel ligands of human xenosensing receptors by the mammalian one-hybrid assay, two cyclohexene-type amide alkaloids were isolated, with nigramide C (NigC) showing the most potent activation of human PXR (hPXR). NigC-mediated hPXR activation was enhanced by overexpression of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor g, coactivator 1a, and protein arginine methyltransferase 1. A direct interaction between the ligand-binding domain of hPXR and the receptor interaction domain of SRC1 was observed. NigC induced the expression of endogenous CYP3A4 mRNA and protein in both cultured hepatoma cells and primary hepatocytes. However, in primary hepatocytes, the relative agonist activity of NigC was not as potent as that of rifampicin, probably because of lower metabolic stability of NigC in these cells. In conclusion, NigC was found to be an effective agonist of hPXR. NigC is a useful tool for investigation of hPXR function.

Picrasidine N Is a Subtype-Selective PPARβ/δ Agonist

“…During the ongoing search for novel natural ligands of nuclear receptors, , PPARβ/δ was focused on. The present study shows that picrasidine N ( 1 ), which is a naturally occurring dimeric alkaloid from Picrasma quassioides Benn.…”

“…15 However, to date, the identification of PPARβ/δ-specific ligands is quite limited, and only a few ligands have been identified, such as GW501516, GW0742, and L165041. 16,17 During the ongoing search for novel natural ligands of nuclear receptors, 18,19 PPARβ/δ was focused on. The present study shows that picrasidine N (1), which is a naturally occurring dimeric alkaloid from Picrasma quassioides Benn.…”

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

“…However, they do not increase the interaction between PXR and SRC1, 2 or 3 [86]. Nigramide, a compound present in pepper, stimulated the interaction PXR-SRC1 [83]. Moreover, genistein, a phytoestrogen found in soy and derived products, and as well as equol, activated PXR and stimulated its interaction with SRC1 [96].…”