Immunosuppressive effects of rutaecarpine in female BALB/c mice

Jeon, Tae Won; Jin, Chun Hua; Lee, Sang Kyu; Jun, In Hye; Kim, Ghee Hwan; Lee, Dong Ju; Jeong, Hye Gwang; Lee, Kyung‐Bok; Jahng, Yurngdong; Jeong, Tae Cheon

doi:10.1016/j.toxlet.2005.12.005

Cited by 20 publications

(7 citation statements)

References 32 publications

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“…In the in vivo time-course study with RUT, DHED, and EOD, a high dose of 80 mg/kg was administered when compared with the doses used in previous studies that demonstrated toxicity of these compounds (Jeon et al, 2006;Zhang et al, 2011). In agreement with the in vitro studies, Cyp1a1 and Cyp1a2 mRNAs were markedly induced after RUT and DHED treatment in Ahr +/+ mice but not in Ahr 2/2 mice, confirming that induction of the CYP1A family genes by both RUT and DHED is dependent on AHR.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang¹,

Yan²,

Sun³

et al. 2018

Drug Metab Dispos

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zhang¹,

Yan²,

Sun³

et al. 2018

Drug Metab Dispos

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“…41 Evodiamine and rutaecarpine inhibited TNF-a and IL-4 protein expressions in RBL-2H3 cells, revealing that these compounds may be effective for allergic diseases such as atopic dermatitis and rhinitis. 42 Two quinolone alkaloids 5 and 6, isolated from E. rutaecarpa exhibited inhibitory effect on leukotriene (LT) biosynthesis in human granulocytes and their effects were comparable to the positive control zileuton (IC 50 10.4 mM). 43 Yarosh et al 44 have observed that a standardized extract of E. rutaecarpa fruits exhibited a significant topical anti-inflammatory activity in methyl nicotinate-induced erythema in human skin.…”

Section: Alkaloidsmentioning

confidence: 98%

Recent developments in anti‐inflammatory natural products

Gautam

Jachak

2009

Medicinal Research Reviews

393

230

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Many of the inflammatory diseases are becoming common in aging society throughout the world. The clinically used anti-inflammatory drugs suffer from the disadvantage of side effects and high cost of treatment (in case of biologics). Alternative to these drugs are traditional medicines and natural products, which offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Since ancient times traditional medicines and phytopharmaceuticals are being used for the treatment of inflammatory and other disorders. The present review article describes anti-inflammatory natural products derived from plants and marine sources reported during last decade. The compounds described belong to different chemical classes such as alkaloids, steroids, terpenoids, polyphenolics, phenylpropanoids, fatty acids and lipids, and various miscellaneous compounds. The attempt is also being made to enumerate the possible leads, e.g. curcumin, resveratrol, baicalein, boswellic acid, betulinic acid, ursolic acid, and oleanolic acid, for further development with the help of structure-activity relationship (SAR) studies and their current status. In addition SAR studies carried out on the anti-inflammatory activity of flavonoid compounds and clinical studies performed on anti-inflammatory natural products are also discussed.

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“…More recently, highly potent evodiamine derivatives were discovered as novel antitumor agents by systemic structure-activity relationship analysis and biologic evaluations (Dong et al, 2012). Despite the therapeutic benefits, immune-mediated toxicity and acute toxicity were reported in mice treated with evodiamine and rutaecarpine (Jeon et al, 2006;Yang et al, 2006). Although the mechanism of immune-mediated toxicity is not clearly understood, a probable causal link between metabolic activation and the onset of immunotoxicity has been established (Jeon et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Activation of the Indoloquinazoline Alkaloids Evodiamine and Rutaecarpine by Human Liver Microsomes: Dehydrogenation and Inactivation of Cytochrome P450 3A4

et al. 2014

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Evodiamine and rutaecarpine are the main active indoloquinazoline alkaloids of the herbal medicine Evodia rutaecarpa, which is widely used for the treatment of hypertension, abdominal pain, angina pectoris, gastrointestinal disorder, and headache. Immunosuppressive effects and acute toxicity were reported in mice treated with evodiamine and rutaecarpine. Although the mechanism remains unknown, it is proposed that metabolic activation of the indoloquinazoline alkaloids and subsequent covalent binding of reactive metabolites to cellular proteins play a causative role. Liquid chromatography-tandem mass spectrometry analysis of incubations containing evodiamine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed formation of a major GSH conjugate which was subsequently indentified as a benzylic thioether adduct on the C-8 position of evodiamine by NMR analysis. Several other GSH conjugates were also detected, including conjugates of oxidized and demethylated metabolites of evodiamine. Similar GSH conjugates were formed in incubations with rutaecarpine. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed dehydrogenation of the 3-alkylindole moiety in evodiamine and rutaecarpine to an electrophile 3-methyleneindolenine. Formation of the evodiamine and rutaecarpine GSH conjugates was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP1A2 and CYP2D6, respectively. It was found that the 3-methyleneindolenine or another reactive intermediate was a mechanism-based inactivator of CYP3A4, with inactivation parameters K I = 29 mM and k inact = 0.029 minute 21, respectively. In summary, these findings are of significance in understanding the bioactivation mechanisms of indoloquinazoline alkaloids, and dehydrogenation of evodiamine and rutaecarpine may cause toxicities through formation of electrophilic intermediates and lead to drug-drug interactions mainly via CYP3A4 inactivation.

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Immunosuppressive effects of rutaecarpine in female BALB/c mice

Cited by 20 publications

References 32 publications

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

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

Recent developments in anti‐inflammatory natural products

Metabolic Activation of the Indoloquinazoline Alkaloids Evodiamine and Rutaecarpine by Human Liver Microsomes: Dehydrogenation and Inactivation of Cytochrome P450 3A4

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