The Experts below are selected from a list of 1515 Experts worldwide ranked by ideXlab platform
Tae Cheon Jeong - One of the best experts on this subject based on the ideXlab platform.
-
phase i and phase ii metabolite identification of Rutaecarpine in freshly isolated hepatocytes from male sprague dawley rats
Archives of Pharmacal Research, 2017Co-Authors: Youra Kang, Yurngdong Jahng, Mi Jeong Kang, Mahesh R. Nepal, Rajina Shakya, Tae Cheon JeongAbstract:Rutaecarpine, an alkaloid originally isolated from Evodia rutaecarpa, has been used for the treatment of gastrointestinal disorders in Asia. In the present study, the phase I and phase II metabolites of Rutaecarpine were investigated in freshly isolated hepatocytes from male Sprague–Dawley rats. The individual metabolites were characterized via liquid chromatography-tandem mass spectrometry. The incubation of Rutaecarpine with freshly isolated hepatocytes for 2 h yielded five major phase I metabolites. In addition, three glucuronide conjugates and four sulfate conjugates were observed. Because the majority of metabolites observed in vivo were identified, freshly isolated hepatocytes might be useful for the identification of certain metabolites formed from drug candidates from a reduced number of experimental animals.
-
Phase I and phase II metabolite identification of Rutaecarpine in freshly isolated hepatocytes from male Sprague–Dawley rats
Archives of Pharmacal Research, 2017Co-Authors: Youra Kang, Yurngdong Jahng, Mi Jeong Kang, Mahesh R. Nepal, Rajina Shakya, Tae Cheon JeongAbstract:Rutaecarpine, an alkaloid originally isolated from Evodia rutaecarpa , has been used for the treatment of gastrointestinal disorders in Asia. In the present study, the phase I and phase II metabolites of Rutaecarpine were investigated in freshly isolated hepatocytes from male Sprague–Dawley rats. The individual metabolites were characterized via liquid chromatography-tandem mass spectrometry. The incubation of Rutaecarpine with freshly isolated hepatocytes for 2 h yielded five major phase I metabolites. In addition, three glucuronide conjugates and four sulfate conjugates were observed. Because the majority of metabolites observed in vivo were identified, freshly isolated hepatocytes might be useful for the identification of certain metabolites formed from drug candidates from a reduced number of experimental animals.
-
protective effect of Rutaecarpine against t bhp induced hepatotoxicity by upregulating antioxidant enzymes via the camkii akt and nrf2 are pathways
Food and Chemical Toxicology, 2017Co-Authors: Yong Pil Hwang, Tae Cheon Jeong, Chul Yung Choi, Young Chul Chung, Hye Gwang JeongAbstract:Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, has been shown to have cytoprotective potential, but the molecular mechanism underlying this activity remains unclear. Our study was designed to investigate the cytoprotective effect of Rutaecarpine against tert-butyl hydroperoxide (t-BHP) and to elucidate its action mechanism of action of Rutaecarpine in a cultured HepG2 cell line and in mouse liver. Rutaecarpine decreased t-BHP–induced reactive oxygen species (ROS) production, cytotoxicity, and apoptosis in HepG2 cells. Pretreatment with Rutaecarpine prior to the injection of t-BHP significantly prevented the increase in serum levels of AST, ALT, and lipid peroxidation in mice liver. It increased the transcriptional activity of NF-E2–related factor 2 (Nrf2) as well as the products of the Nrf2 target genes hemeoxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate cysteine ligase (GCL). Moreover, Rutaecarpine also enhanced the phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase-II (CaMKII). The pharmaceutical inhibitors, such as KN-93 (CaMKII inhibitor) and LY294002 (Akt inhibitor) suppressed Rutaecarpine-induced HO-1 expression and cytoprotection. Our findings identify the CaMKII-PI3K/Akt-Nrf2 cascade as an antioxidant pathway mediating Rutaecarpine signaling and leading to HO-1 expression in hepatocytes.
-
Effects of Rutaecarpine on the metabolism and urinary excretion of caffeine in rats
Archives of Pharmacal Research, 2011Co-Authors: Sudeep R. Bista, Yurngdong Jahng, Mi Jeong Kang, Wonku Kang, Tae Cheon JeongAbstract:Although Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa , has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of Rutaecarpine in rats. Following oral administration of 80 mg/kg Rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by Rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O -deethylase, pentoxyresorufin O -depentylase, and p -nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that Rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.
-
up regulation of cyp1a1 by Rutaecarpine is dependent on aryl hydrocarbon receptor and calcium
Toxicology, 2009Co-Authors: Tae Cheon Jeong, Ji Hye Im, Hye Gwang JeongAbstract:Abstract Rutaecarpine is a quinazolinocarboline alkaloid isolated from a traditional Chinese medicinal fruit, Evodia rutaecarpa . In the present study, we investigated the effect of Rutaecarpine on CYP1A1 expression mediated by [Ca 2+ ] and the AhR pathway in mouse hepatoma Hepa-1c1c7 cells. Rutaecarpine also significantly increased CYP1A1 enzyme activity and mRNA and protein levels. Rutaecarpine markedly induced XRE and AhR binding activity. CH-223191, an AhR antagonist, blocked the Rutaecarpine-induced CYP1A1 enzyme activity and mRNA and protein expression. In addition, Rutaecarpine remarkably induced the phosphorylation of Ca 2+ /calmodulin (CaM)-dependent protein kinase (CaMK). W7 and BAPTA/AM, a CaM antagonist and an intracellular Ca 2+ chelator, respectively, blocked the Rutaecarpine-induced CYP1A1 enzyme activity and mRNA and protein expression. These results indicate that Rutaecarpine induces CYP1A1 expression through AhR- and calcium-dependent mechanisms.
Yuanjian Li - One of the best experts on this subject based on the ideXlab platform.
-
involvement of trpv1 in the expression and release of calcitonin gene related peptide induced by Rutaecarpine
Molecular Medicine Reports, 2018Co-Authors: Yongmei Yang, Yuanjian Li, Dai Li, Qingquan Chen, Limei He, Aiping Wang, Xiaohui LiAbstract:: The traditional Chinese herb Wu-Chu-Yu has been used to treat hypertension for hundreds of years. A previous study indicated that Rutaecarpine was the effective component of Wu‑Chu‑Yu, which lowered blood pressure by elevating the expression level of calcitonin gene‑related peptide (CGRP). The present study was performed to investigate the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) in CGRP expression and release induced by Rutaecarpine. Dorsal root ganglia (DRG) obtained from Sprague‑Dawley rats were cultured to analyze the mRNA expression and release of CGRP. Calcium influx, as an indicator of TRPV1 activation, was measured in 293 cells with stable overexpression of TRPV1. The results demonstrated that the amount of CGRP in the cell culture supernatant and the mRNA expression of CGRPα and CGRPβ in DRG was upregulated by Rutaecarpine in a concentration‑dependent manner, and was inhibited by the TRPV1 receptor antagonist capsazepine. In addition, intracellular Ca2+ levels were increased by Rut in the aforementioned 293 cell line, indicating the activation of TRPV1 by Rut. Therefore, it was concluded that TRPV1 was involved in the expression and release of CGRP stimulated by Rutaecarpine, which provided novel mechanistic understanding of the treatment of hypertension using the Chinese herb Wu-Chu-Yu.
-
Rutaecarpine attenuates hypoxia induced right ventricular remodeling in rats
Naunyn-schmiedebergs Archives of Pharmacology, 2016Co-Authors: Wenqun Li, Dai Li, Xiaohui Li, Jie Du, Wang Zhang, Xiaoming Xiong, Yuanjian LiAbstract:Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of Rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with Rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by Rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8–37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of Rutaecarpine involve the eIF3a/p27 pathway.
-
calcitonin gene related peptide mediates the cardioprotective effects of Rutaecarpine against ischaemia reperfusion injury in spontaneously hypertensive rats
Clinical and Experimental Pharmacology and Physiology, 2009Co-Authors: Dai Li, Hanwu Deng, Xiaojie Zhang, Lei Chen, Zhichun Yang, June Peng, Yuanjian LiAbstract:SUMMARY 1 It has been shown that calcitonin gene-related peptide (CGRP) plays an important role in mediating the cardioprotection exerted by Rutaecarpine in normal animals. The aim of the present study was to determine whether Rutaecarpine is able to decrease the susceptibility of hypertensive animals to ischaemia–reperfusion injury by stimulating CGRP release. 2 Spontaneously hypertensive rats (SHR) were pretreated with Rutaecarpine (20 or 40 mg/kg per day, i.g.) for 18 days and then the heart and thoracic aorta were isolated for cardiac function and vascular relaxation analysis. Blood samples and coronary effluent were collected to measure CGRP levels and creatine kinase activity, respectively. The effect of 10 or 30 µmol/L Rutaecarpine on CGRP release was also examined in isolated aortic rings set up in a homeothermal organ bath. 3 Rutaecarpine treatment resulted in a hypotensive effect in SHR concomitant with increases in plasma CGRP levels. In addition, Rutaecarpine significantly stimulated the release of CGRP from aortic rings. Twenty minutes ischaemia and 30 min reperfusion resulted in a marked decrease in myocardial function and a significant increase in the release of creatine kinase in normal control (Wistar-Kyoto) rats, an effect that was exacerbated in SHR. Similarly, the decreased vasodilator response to acetylcholine (3 10−9 to 10−6 mol/L) in isolated aortic rings from Wistar-Kyoto rats was also aggravated in SHR. Both cardiac function and vasodilator responses were significantly improved in SHR after pretreatment with Rutaecarpine. 4 The results of the present study suggest that the increased cardiac susceptibility to ischaemia–reperfusion injury in SHR is related to decreased plasma CGRP levels and that antihypertensive therapy with Rutaecarpine reverses cardiac susceptibility to reperfusion injury by stimulating CGRP release.
-
synthesis and vasodilator effects of Rutaecarpine analogues which might be involved transient receptor potential vanilloid subfamily member 1 trpv1
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Zhuo Chen, Yuanjian Li, Dai Li, Gaoyun Hu, Jun Chen, Huayong ZhouAbstract:Abstract Rutaecarpine is the major alkaloid component of Wu-Chu-Yu, a well known Chinese herbal drug. It has been reported that Rutaecarpine causes the vasodilator, hypotensive effects by stimulation of CGRP synthesis and release via activation of TRPV1. In present study, 23 Rutaecarpine analogues were designed and synthesized. Then, the vasodilator effects of theses compounds were screened by rat aortic ring experiment. The result showed that the 14-N atom of Rutaecarpine might be the key site for the activity. The 5-carbonyl might make lower contribution to the effect. And simple substitute in indole-ring or quinazoline-ring would not enhance the vasodilator effect unless in proper position with proper group. One of these compounds, 10-methylRutaecarpine, exhibited similar effect with Rutaecarpine. Further functional experiments showed its vasodilator and hypotensive effect were related to the stimulation of CGRP release via activation of TRPV1. The vasodilator effects of these compounds were evaluated and the structure–activity relationship was elucidated for the first time. The results suggested a new direction of valuable TRPV1 agonist as anti-hypertensive drugs.
-
involvement of prolylcarboxypeptidase in the effect of Rutaecarpine on the regression of mesenteric artery hypertrophy in renovascular hypertensive rats
Clinical and Experimental Pharmacology and Physiology, 2009Co-Authors: Si-yu Zeng, Yuanjian Li, Dai Li, Haihong Tian, Shuixiu Deng, Yuanbin Zheng, Duanfang Liao, Shiyou ChenAbstract:1. Previous studies indicate that Rutaecarpine blocks the elevation of blood pressure and inhibits vascular hypertrophy in experimental hypertensive rats. The present study is to explore whether the effect of Rut is related to the activation of prolylcarboxypeptidase (PRCP). 2. Renovascular hypertensive rats (Goldblatt two-kidney, one-clip (2K1C)) were developed using the male Sprague-Dawley rats. Chronic treatment with Rutaecarpine (10 or 40mg/kg per day) or losartan (20mg/kg per day) for 4 weeks to the hypertensive rats caused a sustained dose-dependent repression of blood pressure, increased the lumen diameter and decreased the medium thickness, which was companied by a similar reduction in the media cross-sectional area: lumen area ratio in mesenteric arteries compared with untreated hypertensive rats. 3. Angiotensin (Ang) II expression was significantly increased in the mesenteric arteries of hypertensive rats compared with sham-operated rats. No significant differences in plasma Ang II levels were observed between untreated hypertensive and sham-operated rats. The hypertensive rats treated with Rutaecarpine showed a decreased trend of Ang II levels and the high-dose Rutaecarpine decreased significantly Ang II levels in both plasma and mesenteric arteries. 4. Expression of PRCP protein or kallikrein mRNA expression was significantly inhibited in the right kidneys and mesenteric arteries of hypertensive rats. However, expression of PRCP protein or kallikrein mRNA was significantly increased after treatment with Rutaecarpine or losartan (20 mg/kg per day). 5. The data suggest that the repression of increases in systolic blood pressure and reversal of mesenteric artery remodeling by Rutaecarpine may be related to the increased expression of PRCP in the circulation and small arteries in the 2K1C hypertensive rats.
Yurngdong Jahng - One of the best experts on this subject based on the ideXlab platform.
-
phase i and phase ii metabolite identification of Rutaecarpine in freshly isolated hepatocytes from male sprague dawley rats
Archives of Pharmacal Research, 2017Co-Authors: Youra Kang, Yurngdong Jahng, Mi Jeong Kang, Mahesh R. Nepal, Rajina Shakya, Tae Cheon JeongAbstract:Rutaecarpine, an alkaloid originally isolated from Evodia rutaecarpa, has been used for the treatment of gastrointestinal disorders in Asia. In the present study, the phase I and phase II metabolites of Rutaecarpine were investigated in freshly isolated hepatocytes from male Sprague–Dawley rats. The individual metabolites were characterized via liquid chromatography-tandem mass spectrometry. The incubation of Rutaecarpine with freshly isolated hepatocytes for 2 h yielded five major phase I metabolites. In addition, three glucuronide conjugates and four sulfate conjugates were observed. Because the majority of metabolites observed in vivo were identified, freshly isolated hepatocytes might be useful for the identification of certain metabolites formed from drug candidates from a reduced number of experimental animals.
-
Phase I and phase II metabolite identification of Rutaecarpine in freshly isolated hepatocytes from male Sprague–Dawley rats
Archives of Pharmacal Research, 2017Co-Authors: Youra Kang, Yurngdong Jahng, Mi Jeong Kang, Mahesh R. Nepal, Rajina Shakya, Tae Cheon JeongAbstract:Rutaecarpine, an alkaloid originally isolated from Evodia rutaecarpa , has been used for the treatment of gastrointestinal disorders in Asia. In the present study, the phase I and phase II metabolites of Rutaecarpine were investigated in freshly isolated hepatocytes from male Sprague–Dawley rats. The individual metabolites were characterized via liquid chromatography-tandem mass spectrometry. The incubation of Rutaecarpine with freshly isolated hepatocytes for 2 h yielded five major phase I metabolites. In addition, three glucuronide conjugates and four sulfate conjugates were observed. Because the majority of metabolites observed in vivo were identified, freshly isolated hepatocytes might be useful for the identification of certain metabolites formed from drug candidates from a reduced number of experimental animals.
-
progress in studies on Rutaecarpine ii synthesis and structure biological activity relationships
Molecules, 2015Co-Authors: Hyeun Wook Chang, Yurngdong JahngAbstract:Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on Rutaecarpine have included isolation from new natural sources, development of new synthetic methods for its total synthesis, the discovery of new biological activities, metabolism, toxicology, and establishment of analytical methods for determining Rutaecarpine content. The present review focuses on the synthesis, biological activities, and structure-activity relationships of Rutaecarpine derivatives, with respect to their antiplatelet, vasodilatory, cytotoxic, and anticholinesterase activities.
-
Effects of Rutaecarpine on the metabolism and urinary excretion of caffeine in rats
Archives of Pharmacal Research, 2011Co-Authors: Sudeep R. Bista, Yurngdong Jahng, Mi Jeong Kang, Wonku Kang, Tae Cheon JeongAbstract:Although Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa , has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of Rutaecarpine in rats. Following oral administration of 80 mg/kg Rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by Rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O -deethylase, pentoxyresorufin O -depentylase, and p -nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that Rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.
-
Short communication: in vivo evaluation of microemulsion system for oral and parenteral delivery of Rutaecarpine to rats.
Drug Development and Industrial Pharmacy, 2008Co-Authors: Chul-soon Yong, Yurngdong Jahng, Byung-joo Park, Krisna Bhamdari, Hangon ChoiAbstract:ABSTRACTRutaecarpine-loaded microemulsion composed of 10.8% polyethylene glycol 400, 7.2% Tween 80, 20% caster oil, and 62% water were previously reported to be physically and chemically stable for at least 6 months. For the development of a Rutaecarpine-loaded microemulsion, here we studied the pharmacokinetic profiles of Rutaecarpine after oral and intravenous administration of Rutaecarpine-loaded microemulsion compared to suspension. The AUC of Rutaecarpine from microemulsion after oral and intravenous administration increased about three-fold compared with that from suspension. Furthermore, the Rutaecarpine-loaded microemulsion gave significantly higher AUC and Cmax than did suspension, suggesting that the oral bioavailability of Rutaecarpine in this microemulsion system could be enhanced due to the enhanced solubility of Rutaecarpine by microemulsion. Thus, our results indicated that the microemulsion system composed of castor oil, polyethylene glycol 400, Tween 80, and water could be a more effectiv...
Chiehfu Chen - One of the best experts on this subject based on the ideXlab platform.
-
elimination of Rutaecarpine and its metabolites in rat feces and urine measured by liquid chromatography
Biomedical Chromatography, 2006Co-Authors: Chiehfu Chen, Tunghu TsaiAbstract:Rutaecarpine is an alkaloid isolated from the medicinal herb Evodia rutaecarpa. This study was to evaluate the elimination pathway of Rutaecarpine in rat feces and urine. Rutaecarpine and its metabolites (3-, 10-, 11- and 12-hydroxyRutaecarpine) in urine were measured after incubation with β-glucuronidase. After the Rutaecarpine was administered (25 and 100 mg/kg) orally to rats, the urine and fecal samples were collected using a metabolic cage for five consecutive days. For determining Rutaecarpine, the mobile phase consisted of acetontrile–10 mM NaH2PO4 (60:40, v/v, pH 4.2 adjusted with orthophosphoric acid) with a flow rate of 1 mL/min. The calibration curve was linear in concentrations of 0.05–50 µg/mL in fecal and urine sample. The results indicated that more than 42% of the Rutaecarpine was excreted by feces after oral administration (25 and 100 mg/kg), but only a small amount of Rutaecarpine was detected in urine at a higher dose of Rutaecarpine (100 mg/kg). After incubation with β-glucuronidase, the hydroxyRutaecarpine in urine was eluted using methanol–acetonitrile–0.04% formic acid (6:30:64, v/v) with a flow rate of 1.2 mL/min. We conclude that the metabolic pathway of Rutaecarpine went through phase I hydroxylation and phase II conjugation, and the major metabolite is 10-hydroxyRutaecarpine eliminated from urine of the rat. Copyright © 2006 John Wiley & Sons, Ltd.
-
oxidative metabolism of the alkaloid Rutaecarpine by human cytochrome p450
Drug Metabolism and Disposition, 2006Co-Authors: Yune-fang Ueng, Li Kang Ho, Shuyun Wang, Chiehfu ChenAbstract:Rutaecarpine is the main active alkaloid of the herbal medicine, Evodia rutaecarpa . To identify the major human cytochrome P450 (P450) participating in Rutaecarpine oxidative metabolism, human liver microsomes and bacteria-expressed recombinant human P450 were studied. In liver microsomes, Rutaecarpine was oxidized to 10-, 11-, 12-, and 3-hydroxyRutaecarpine. Microsomal 10- and 3-hydroxylation activities were strongly inhibited by ketoconazole. The 11- and 12-hydroxylation activities were inhibited by α-naphthoflavone, quinidine, and ketoconazole. These results indicated that multiple hepatic P450s including CYP1A2, CYP2D6, and CYP3A4 participate in Rutaecarpine hydroxylations. Among recombinant P450s, CYP1A1 had the highest Rutaecarpine hydroxylation activity. Decreased metabolite formation at high substrate concentration indicated that there was substrate inhibition of CYP1A1- and CYP1A2-catalyzed hydroxylations. CYP1A1-catalyzed Rutaecarpine hydroxylations had V max values of 1388 to ∼1893 pmol/min/nmol P450, K m values of 4.1 to ∼9.5 μM, and K i values of 45 to ∼103 μM. These results indicated that more than one molecule of Rutaecarpine is accessible to the CYP1A active site. The major metabolite 10-hydroxyRutaecarpine decreased CYP1A1, CYP1A2, and CYP1B1 activities with respective IC 50 values of 2.56 ± 0.04, 2.57 ± 0.11, and 0.09 ± 0.01 μM, suggesting that product inhibition might occur during Rutaecarpine hydroxylation. The metabolite profile and kinetic properties of Rutaecarpine hydroxylation by human P450s provide important information relevant to the clinical application of Rutaecarpine and E. rutaecarpa .
-
identification of the microsomal oxidation metabolites of Rutaecarpine a main active alkaloid of the medicinal herb evodia rutaecarpa
Journal of Chromatography A, 2005Co-Authors: Yune-fang Ueng, Li Kang Ho, Hsi-jung Yu, Ching Peng, Chiehfu ChenAbstract:Abstract Rutaecarpine is a quinazolinocarboline alkaloid of the medicinal herb Evodia rutaecarpa and shows a variety of pharmacological effects. Four oxidation metabolites of Rutaecarpine were prepared from 3-methylcholanthrene-treated rat liver microsomes. These metabolites had an [M + H] + ion at m / z 304. The structures of metabolites were identified by comparison of their liquid chromatograms and mass, absorbance, and 1 H NMR spectra with those of synthetic standards. Rutaecarpine was metabolized by microsomal enzymes to form 3-, 10-, 11-, and 12-hydroxyRutaecarpine. The formation of 10-hydroxyRutaecarpine was highly induced by a cytochrome P450 1A inducer, 3-methylcholanthrene.
-
the alkaloid Rutaecarpine is a selective inhibitor of cytochrome p450 1a in mouse and human liver microsomes
Drug Metabolism and Disposition, 2002Co-Authors: Yune-fang Ueng, Taliang Chen, Peter F Guengerich, Chiehfu ChenAbstract:Rutaecarpine, evodiamine, and dehydroevodiamine are quinazolinocarboline alkaloids isolated from a traditional Chinese medicine, Evodia rutaecarpa. The in vitro effects of these alkaloids on cytochrome P450 (P450)-catalyzed oxidations were studied using mouse and human liver microsomes. Among these alkaloids, Rutaecarpine showed the most potent and selective inhibitory effect on CYP1A-catalyzed 7-methoxyresorufin O-demethylation (MROD) and 7-ethoxyresorufin O-deethylation (EROD) activities in untreated mouse liver microsomes. The IC50 ratio of EROD to MROD was 6. For MROD activity, Rutaecarpine was a noncompetitive inhibitor with aKi value of 39 ± 2 nM. In contrast, Rutaecarpine had no effects on benzo[a]pyrene hydroxylation (AHH), aniline hydroxylation, and nifedipine oxidation (NFO) activities. In human liver microsomes, 1 μM Rutaecarpine caused 98, 91, and 77% decreases of EROD, MROD, and phenacetinO-deethylation activities, respectively. In contrast, less than 15% inhibition of AHH, tolbutamide hydroxylation, chlorzoxazone hydroxylation, and NFO activities were observed in the presence of 1 μM Rutaecarpine. To understand the selectivity of inhibition of CYP1A1 and CYP1A2, inhibitory effects of Rutaecarpine were studied using liver microsomes of 3-methylcholanthrene (3-MC)-treated mice and Escherichia coli membrane expressing bicistronic human CYP1A1 and CYP1A2. Similar to the CYP1A2 inhibitor furafylline, Rutaecarpine preferentially inhibited MROD more than EROD and had no effect on AHH in 3-MC-treated mouse liver microsomes. For bicistronic human P450s, the IC50 value of Rutaecarpine for EROD activity of CYP1A1 was 15 times higher than the value of CYP1A2. These results indicated that Rutaecarpine was a potent inhibitor of CYP1A2 in both mouse and human liver microsomes.
-
induction of cytochrome p450 dependent monooxygenase in mouse liver and kidney by Rutaecarpine an alkaloid of the herbal drug evodia rutaecarpa
Life Sciences, 2001Co-Authors: Yune-fang Ueng, Jongjing Wang, Sang Shin Park, Chiehfu ChenAbstract:Rutaecarpine is one of the main alkaloids of an herbal remedy, Evodia rutaecarpa, which has been used for the treatment of gastrointestinal disorder and headache. Effects of Rutaecarpine on hepatic and renal cytochrome P450 (CYP)-dependent monooxygenase were studied in C57BL/6J mice. Treatment of mice with Rutaecarpine by gastrogavage at 50 mg/kg/day for three days resulted in 57%, 41%, 6-, and 6-fold increases of hepatic microsomal benzo(a)pyrene hydroxylation, 7-ethoxycoumarin O-deethylation, 7-ethoxyresorufin O-deethylation, and 7-methoxyresorufin O-demethylation activities, respectively. However, the treatment had no effects on hepatic oxidation activities toward benzphetamine, N-nitrosodimethylamine, nifedipine, and erythromycin. In the kidney, Rutaecarpine-treatment resulted in 2-fold and 42% increases of microsomal benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation activities, respectively. The treatment also increased renal 7-ethoxyresorufin O-deethylation activity to a detectable level. Immunoblot analysis of microsomal proteins showed that Rutaecarpine-treatment increased the protein levels of CYP1A1 and CYP1A2 in the liver, whereas hepatic level of CYP3A-immunoreacted protein was not affected by Rutaecarpine. These CYPs were not detectable in the immunoblot analyses of control and Rutaecarpine-treated mouse kidney microsomes. These results indicated that Rutaecarpine was a CYP1A inducer and showed potent inductive effects on both CYP1A1 and CYP1A2 in the liver.
Changping Hu - One of the best experts on this subject based on the ideXlab platform.
-
pharmacological effects of Rutaecarpine as a cardiovascular protective agent
Molecules, 2010Co-Authors: Changping HuAbstract:Many studies indicate that traditional Chinese herbs are beneficial in the prevention and treatment of cardiovascular diseases. Evodia rutaecarpa ('Wu-Chu-Yu') remains the most popular and multi-purpose herb traditionally used in China for treatment of headache, abdominal pain, postpartum hemorrhage, dysentery and amenorrhea. Rutaecarpine is one of the intriguing indolopyridoquinazoline alkaloids isolated from 'Wu-Chu-Yu'. Rutaecarpine has been shown to have cardiovascular biological effects such as inotropic and chronotropic, vasorelaxant, anti-platelet aggregation and anti-inflammatory effects. Furthermore, it has been reported that Rutaecarpine has beneficial effects on some cardiovascular diseases. This review summarizes data on the cardiovascular pharmacological actions of Rutaecarpine the published over the recent years, aiming to provide more evidence supporting its use in the treatment of cardiovascular diseases.
-
the protective effects of Rutaecarpine on gastric mucosa injury in rats
Planta Medica, 2005Co-Authors: Li Wang, Changping Hu, Panyue Deng, Shensi Shen, Jin Song Ding, Yuanjian LiAbstract:: Previous investigations have shown that calcitonin gene-related peptide (CGRP) protects gastric mucosa against injury induced by acetylsalicylic acid (ASA) and that Rutaecarpine activates vanilloid receptors to evoke CGRP release. In the present study, we examined the protective effects of Rutaecarpine on gastric mucosa injury, and explored whether the protective effects of Rutaecarpine are related to stimulation of endogenous CGRP release via activating vanilloid receptors in rats. In an ASA-induced ulceration model, gastric mucosal ulcer index, pH value of gastric juice and plasma concentrations of CGRP were determined. ASA significantly increased the gastric mucosal ulcer index and the back-diffusion of H+ through the mucosa. Rutaecarpine at the doses of 100 or 300 microg/kg (i.v.), and 300 or 600 microg/kg (intragastric, i.g.) reduced the ulcer index and back-diffusion of H+, which was abolished by pretreatment with capsaicin (50 mg/kg, s.c.) or capsazepine (3 mg/kg, i.v.), a competitive vanilloid receptor antagonist. Rutaecarpine significantly increased the plasma concentration of CGRP, which was also abolished by capsazepine. In a stress-induced ulceration model, Rutaecarpine reduced gastric mucosal damages, which was abolished by capsazepine (5 mg/kg, i.p.). These results suggest that Rutaecarpine protects the gastric mucosa against injury induced by ASA and stress, and that the gastroprotective effect of Rutaecarpine is related to a stimulation of endogenous CGRP release via activation of the vanilloid receptor.
-
Involvement of CGRP in the inhibitory effect of Rutaecarpine on vasoconstriction induced by anaphylaxis in guinea pig.
Regulatory peptides, 2005Co-Authors: Jing Yu, Changping Hu, Panyue Deng, Kang Ping Xu, Yuanjian LiAbstract:Previous investigations have indicated that calcitonin gene-related peptide (CGRP), a principal transmitter in capsaicin-sensitive sensory nerves, could alleviate cardiac anaphylaxis injury. Rutaecarpine relaxes vascular smooth by stimulation of CGRP release via activation of vanilloid receptor subtype 1 (VR1). In the present study, we examined the role of capsaicin-sensitive sensory nerves in anaphylactic vessels and the effect of Rutaecarpine on antigen-challenged constriction in the guinea pig isolated thoracic aorta. The aortas were challenged with 0.01 mg/ml bovine serum albumin, and the tension of aorta rings was continuously monitored. The amount of CGRP released from thoracic aortas was determined in the absence or presence of Rutaecarpine. Antigen challenge caused a vasoconstrictor response concomitantly with an increase in the release of CGRP from the isolated thoracic aorta, and the vasoconstrictor responses were potentiated by CGRP8-37 (10 microM) or capsaicin (1 microM). Pretreatment with diphenhydramine (1 microM) markedly decreased antigen-challenged vasoconstriction. Acute application of capsaicin (0.03 or 0.1 microM) significantly inhibited vasoconstrictor responses. Pretreatment with Rutaecarpine (10 or 30 microM) significantly increased CGRP release concomitantly with decrease in antigen-challenged vasoconstriction, which was abolished by CGRP8-37 (10 microM) or capsazepine (10 microM). The present results suggest that an increase in the release of CGRP during vascular anaphylaxis may be a beneficial compensatory response, and that Rutaecarpine inhibits antigen-challenged vasoconstriction, which is related to stimulation of endogenous CGRP release via activation of VR1.
-
protective effects of Rutaecarpine in cardiac anaphylactic injury is mediated by cgrp
Planta Medica, 2004Co-Authors: Hong Hui Yi, Changping Hu, Panyue Deng, Wei Qing Rang, Kang Ping Xu, Yuanjian LiAbstract:: Previous investigations have indicated that Rutaecarpine activates the vanilloid receptor to evoke calcitonin gene-related peptide (CGRP) release. CGRP has been shown to alleviate cardiac anaphylactic injury. In the present study, the effect of Rutaecarpine on cardiac anaphylaxis was examined. Challenge of presensitized guinea-pig hearts with a specific antigen caused marked decreases in coronary flow (CF), left ventricular pressure (LVP) and its derivatives (+/- dp/dt(max)), an increase in heart rate, and prolongation of the P-R interval. Rutaecarpine (0.3 or 1 microM) markedly increased the content of calcitonin gene-related peptide (CGRP) in the coronary effluent and decreased the content of tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues concomitantly with a significant improvement of cardiac function and alleviation of the extension of the P-R interval. Rutaecarpine at the concentration of 1 microM also inhibited the sinus tachycardia. The protective effects of Rutaecarpine on cardiac anaphylaxis were abolished by CGRP (8-37), a selective CGRP receptor antagonist. These results suggest that the protective effects of Rutaecarpine on cardiac anaphylactic injury are related to inhibition of TNF-alpha production by stimulation of CGRP release.
-
involvement of capsaicin sensitive sensory nerves in cardioprotection of Rutaecarpine in rats
Regulatory Peptides, 2003Co-Authors: Changping Hu, Niansheng Li, Liang Xiao, Hanwu Deng, Yuanjian LiAbstract:In the present study, we examined whether Rutaecarpine protects against myocardial ischemia-reperfusion injury in rats and whether the protective effects of Rutaecarpine are related to activation of capsaicin-sensitive sensory nerves. Rats were pretreated with Rutaecarpine 10 min before the experiment, and then the left main coronary artery of rat hearts was subjected to 60-min occlusion followed by 3-h reperfusion. The infarct size, serum concentration of creatine kinase, and CGRP concentration in plasma were measured. Pretreatment with Rutaecarpine (100 or 300 μg/kg, i.v.) significantly reduced infarct size and creatine kinase release concomitantly with a significant increase in plasma concentrations of CGRP. These effects of Rutaecarpine were completely abolished by capsazepine (38 mg/kg, s.c.), a competitive vanilloid receptor antagonist, or by pretreatment with capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. These results suggest that Rutaecarpine protects against myocardial ischemia-reperfusion injury in rats and that the protective effects of Rutaecarpine are related to activation of capsaicin-sensitive sensory nerves via activating vanilloid receptors.
