Isosilybin (Isosilybinin) is a flavonoid from milk thistle; inhibits CYP3A4 induction with an IC50 of 74 μM.
The reporter gene assay shows that milk thistle’s components silybin and isosilybin are responsible for the inhibition of PXR-mediated CYP3A4 induction by milk thistle. Compared with silybin, its isomer isosilybin is a stronger inhibitor of PXR-mediated CYP3A4 induction. A solution of 89, 133, and 200 μM isosilybin significantly inhibits CYP3A4 induction by 64, 82, and 88%, respectively. Isosilybin inhibits CYP3A4 induction with an IC50 of 74 μM[1]. Isosilybin B and isosilybin A, two diastereoisomers isolated from silymarin, have anti-prostate cancer (PCA) activity that is mediated via cell cycle arrest and apoptosis induction. Isosilybin B and isosilybin A treatment results in growth inhibition and cell death together with a strong G(1) arrest and apoptosis in human prostate cancer LNCaP and 22Rv1 cells[2]. Isosilybin B causes increased phosphorylation of Akt (Ser-473 and Thr-308) and Mdm2 (Ser-166), which is linked with androgen receptor degradation as pretreatment with PI3K inhibitor (LY294002)-restored androgen receptor level. Isosilybin B treatment enhances the formation of complex between Akt, Mdm2 and AR, which promotes phosphorylation-dependent AR ubiquitination and its degradation by proteasome[3]. Isosilybin A is able to significantly activate PPARγ at a concentration of 30 μM (2.08±0.48 fold, p<0.01). Isosilybin A causes transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. In silico docking studies suggests a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor[4].
References:
[1]. Mooiman KD, et al. Milk thistle's active components silybin and isosilybin: novel inhibitors of PXR-mediated CYP3A4 induction. Drug Metab Dispos. 2013 Aug;41(8):1494-504.
[2]. Deep G, et al. Isosilybin B and isosilybin A inhibit growth, induce G1 arrest and cause apoptosis in human prostate cancer LNCaP and 22Rv1 cells. Carcinogenesis. 2007 Jul;28(7):1533-42.
[3]. Deep G, et al. Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway. Oncogene. 2008 Jun 26;27(28):3986-98.
[4]. Pferschy-Wenzig EM, et al. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma. J Nat Prod. 2014 Apr 25;77(4):842-7.