Structure-Activity Relationships of the Main Bioactive Constituents of Euodia rutaecarpa on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis

Abstract

Rutaecarpine (RUT), evodiamine (EOD), and dehydroevodiamine (DHED) are the three main bioactive indoloquinazoline alkaloids isolated from , a widely prescribed traditional Chinese medicine. Here, the structure-activity relationships of these analogs for aryl hydrocarbon receptor (AHR) activation were explored by use of-deficient () mice, primary hepatocyte cultures, luciferase reporter gene assays, in silico ligand-docking studies, and metabolomics. In vitro, both mRNA analysis of AHR target genes in mouse primary hepatocytes and luciferase reporter assays in hepatocarcinoma cell lines demonstrated that RUT, EOD, and DHED significantly activated AHR, with an efficacy order of RUT > DHED > EOD. Ligand-docking analysis predicted that the methyl substitute at the N-14 atom was a key factor affecting AHR activation. In vivo, EOD was poorly orally absorbed and failed to activate AHR, whereas RUT and DHED markedly upregulated expression of the hepatic AHR gene battery in wild-type mice, but not in mice. Furthermore, RUT, EOD, and DHED were not hepatotoxic at the doses used; however, RUT and DHED disrupted bile acid homeostasis in an AHR-dependent manner. These findings revealed that the methyl group at the N-14 atom of these analogs and their pharmacokinetic behaviors were the main determinants for AHR activation, and suggest that attention should be given to monitoring bile acid metabolism in the clinical use of.

Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway

“…Regarding the interaction of rutaecarpine with AhR, we provide both theoretical and experimental evidence demonstrating that rutaecarpine is a promising natural stimulant of mouse and human AhR. The results of molecular docking simulation showed that rutaecarpine was capable to interact with AhR, which is consistent with the molecular docking results of Zhang Y. et al (2018) . The binding mode of rutaecarpine is through interaction with residues outside the binding site instead of getting into the binding pocket of AhR.…”

“…Evodiamine, dehydroevodiamine, and rutaecarpine are three major bioactive components of Evodia rutaecarpine ( Zhang Y. et al, 2018 ; Zhang et al, 2020 ). Their effects on cardiovascular protection, hepatic lipid metabolism regulation, liver injury protection, degenerative neurological diseases improvement, and acute pancreatitis protection have been fully recorded ( Yan et al, 2018 ; Tian et al, 2019 ; Li et al, 2020 ; Zhao B. et al, 2020 ).…”

“… Gillner et al (1989) proposed that rutaecarpine has the common molecular structure characteristics of most high-affinity ligands of AhR via molecular mapping analysis, after that the AhR-binding ability of rutaecarpine was further evidenced by evaluating the DRE-related transcription activity via a reporter gene system and the expression of the AhR downstream gene CYP1A1 in rutaecarpine-treated mouse Hepa-1c1c7 cells. In addition, compared with the other two major compounds derived from Evodia rutaecarpa , evodiamine or dehydroevodiamine, rutaecarpine might be a more effective ligand of AhR ( Han et al, 2009 ; Zhang Y. et al, 2018 ). Therefore, rutaecarpine might be a promising AhR agonist for further evaluating its effect on glioblastoma cell migration.…”

Poly‐pharmacokinetic strategy represented the synergy effects of bioactive compounds in a traditional Chinese medicine formula, Si Shen Wan and its separated recipes to normal and colitis rats

“…Many studies related to these four herbs have been conducted in our previous researches, including studies of the chemical composition [11], pharmacokinetics (PK) [12], pharmacology [13], and clinical application [14]. It is worth to mention that the systematic phytochemical investigations of the main constituents of PC, MF, and ER were clarified.…”

“…from Beijing John Long Technology Development (Beijing, China) and Chengdu Push Biotechnology (Chengdu, China), respectively. (-)-Licarin-B (2) [30], isopsoralen (8), psoralen (9), psoralidin (1), lespecyrtin B1 (3), isobavachromene (4), isobavachalcone (5), psorachalcone A (6), bavachin (7), neobavaisoflavone (15) [18,20,21,[31][32][33], 10-methoxywuchuyuamide I (10), dehydroevodiamine (11), wuchuyuamide-I (12), wuchuyuamide-III (14), evodiame (16), rutaecarpine (19), evocarpine (23), 1-methyl-2-decyl-4(1H)-quinolone (26) [34][35][36] were isolated from PC, MF, EF in our laboratory with the purity ≥98% which the structure identification were completed by 1 H-NMR, 13 C-NMR, and TOF-MS spectral analyses as described in our previous reports. Carbamazepine (Internal standard, IS, Cat No.…”