PT  - JOURNAL ARTICLE
AU  - Youbo Zhang
AU  - Tingting Yan
AU  - Dongxue Sun
AU  - Cen Xie
AU  - Yiran Zheng
AU  - Lei Zhang
AU  - Tomoki Yagai
AU  - Kristopher W Krausz
AU  - William H Bisson
AU  - Xiuwei Yang
AU  - Frank J Gonzalez
TI  - Structure-activity relationships of the main bioactive constituents of Euodia ruticarpa on aryl hydrocarbon receptor activation and bile acid homeostasis
AID  - 10.1124/dmd.117.080176
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.080176
4099  - http://dmd.aspetjournals.org/content/early/2018/04/24/dmd.117.080176.short
4100  - http://dmd.aspetjournals.org/content/early/2018/04/24/dmd.117.080176.full
AB  - Rutaecarpine (RUT), evodiamine (EOD) and dehydroevodiamine (DHED), are the three main bioactive indoloquinazoline alkaloids isolated from Euodia ruticarpa, a widely prescribed traditional Chinese medicine. Here, the structure-activity relationships of these analogues for aryl hydrocarbon receptor (AHR) activation were explored by use of Ahr-deficient (Ahr-/-) 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, while RUT and DHED markedly upregulated the hepatic AHR battery gene expression in wild-type mice, but not in Ahr-/- mice. Furthermore, RUT, EOD and DHED were not hepatoxic at the doses employed, 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 analogues 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 Euodia ruticarpa.