Identification of the microsomal oxidation metabolites of rutaecarpine, a main active alkaloid of the medicinal herb Evodia rutaecarpa

Ueng, Yune-Fang; Yu, Hai-Chin; Lee, Chang-Hsin; Peng, Ching; Jan, Woan-Ching; Ho, Li-Kang; Chen, Chieh-Fu; Don, Ming‐Jaw

doi:10.1016/j.chroma.2005.04.021

Cited by 28 publications

(36 citation statements)

References 11 publications

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“…Such a two-step oxidation mechanism has been proposed for the bioactivation of 3-methylindole (Yan et al, 2007) and other compounds forming p-aminophenol metabolites, such as diclofenac (Shen et al, 1999;Poon et al, 2001) and lumiracoxib (Li et al, 2008;Kang et al, 2009). This was in parallel with previous studies wherein such hydroxylated metabolites of evodiamine and rutaecarpine were detected in liver microsomes (Ueng et al, 2005(Ueng et al, , 2006Sun et al, 2013). The reactive iminoquinone species would covalently modify nucleophilic residues of cellular proteins and/or P450 enzymes leading to toxicity and enzyme inactivation.…”

supporting

confidence: 73%

“…In addition to aromatic and aliphatic hydroxylation, other metabolic pathways including N-demethylation of evodiamine were observed (Sun et al, 2013). Of particular interest in the metabolism pathways of rutaecarpine is the detection of 10-and 12-hydroxy metabolites of rutaecarpine (Ueng et al, 2005;Lee et al, 2006b). 10-Hydroxyrutaecarpine and 12-hydroxyrutaecarpine can undergo P450-mediated two-electron oxidations to form electrophilic para-and ortho-quinone imine intermediates, respectively, which are capable of reacting with cellular proteins and other nucleophiles, such as glutathione.…”

Section: Introductionmentioning

confidence: 99%

“…Rutaecarpine undergoes extensive oxidative metabolism in human and rat liver microsomes mainly by aromatic hydroxylation to form 3-, 10-, 11-, and 12-hydroxyrutaecarpine (Ueng et al, 2005(Ueng et al, , 2006Lee et al, 2006b) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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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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supporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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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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“…18.6, 11.9, and 6.9 min, respectively. 10-Hydroxyrutaecarpine was identified and confirmed by using liquid chromatography-electrospray ionization tandem mass spectrometry and by previous literatures , Ueng et al, 2005.…”

Section: Resultsmentioning

confidence: 99%

Effect of Phenobarbital on the Pharmacokinetics of Rutaecarpine and its Metabolite in Rats

Kim¹,

Lee²,

Seo³

et al. 2008

Biomolecules and Therapeutics

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− To investigate the possible interaction between rutaecarpine and phenobarbital in rats, phenobarbital in saline at 80 mg/kg was given ip to male SD rats for 3 consecutive days. Saline was given to control animals. One day after phenobarbital pre-treatment, rutaecarpine at 16 mg/kg was administered through penile vein. Blood was collected and analyzed by using HPLC. The pharmacokinetic parameters were determined with the non-compartmental model. Pre-treatment with phenobarbital significantly altered the pharmacokinetic profiles of rutaecarpine and its metabolite, 10-hydroxyrutaecarpine. The AUC of rutaecarpine was reduced to approximately 50% of control and the plasma half-life of rutaecarpine was significantly shortened when compared with control. In addition, the Cmax of 10-hydroxyrutaecarpine was increased approximately 160% of control. The AUC and the plasma half-life of 10-hydroxyrutaecarpine were decreased to 76.9% of control and to 82.7 min from 175.9 min, respectively. The results suggested that phenobarbital might accelerate the metabolism of rutaecarpine, thereby changing the pharmacokinetic parameters of rutaecarpine in male SD rats.

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“…13) Ueng et al reported recently that 11-hydroxyrutaecarpine was one of the oxidation metabolites of rutaecarpine by liver microsomal enzymes in rats. 8) In general, xenobiotic hydroxylation metabolites have higher hydrophilicity than their parent compounds and show less biological activities or toxicities. It is clear that compounds 1 and 2 with more glycosyl than 11-hydroxyrutaecarpine showed higher hydrophilicity.…”

Section: Resultsmentioning

confidence: 99%

Two New Indolopyridoquinazoline Alkaloidal Glycosides from Ranunculus ternatus

2007

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Identification of the microsomal oxidation metabolites of rutaecarpine, a main active alkaloid of the medicinal herb Evodia rutaecarpa

Cited by 28 publications

References 11 publications

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

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

Effect of Phenobarbital on the Pharmacokinetics of Rutaecarpine and its Metabolite in Rats

Two New Indolopyridoquinazoline Alkaloidal Glycosides from Ranunculus ternatus

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