The Alkaloid Rutaecarpine Is a Selective Inhibitor of Cytochrome P450 1A in Mouse and Human Liver Microsomes

Ueng, Yune-Fang; Jan, Woan Ching; Lin, Lie Chwen; Chen, Ta-Liang; Guengerich, F. Peter; Chen, Chieh Fu

doi:10.1124/dmd.30.3.349

Cited by 65 publications

(36 citation statements)

References 25 publications

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“…observed with tolbutamide hydroxylase (CYP2C9), chlorzoxazone hydroxylase (CYP2E1), and nifedipine oxidase (CYP3A4) activities (Ueng et al, 2002). Similar to the CYP1A2 inhibitor furafylline, rutaecarpine preferentially inhibited 7-methoxyresorufin O-demethylase more than 7-ethoxyresorufin O-deethylase and had no effect on aryl hydrocarbon hydroxylase in 3-methylcholanthrene-treated mouse liver microsomes, indicating that rutaecarpine was a potent inhibitor of CYP1A2 in vitro.…”

Section: Zhou Et Al 58mentioning

confidence: 94%

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Interactions of Herbs with Cytochrome P450

Zhou

Gao²,

Jiang

et al. 2003

Drug Metabolism Reviews

358

207

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A resurgence in the use of medical herbs in the Western world, and the co-use of modern and traditional therapies is becoming more common. Thus there is the potential for both pharmacokinetic and pharmacodynamic herb-drug interactions. For example, systems such as the cytochrome P450 (CYP) may be particularly vulnerable to modulation by the multiple active constituents of herbs, as it is well known that the CYPs are subject to induction and inhibition by exposure to a wide variety of xenobiotics. Using in vitro, in silico, and in vivo approaches, many herbs and natural compounds isolated from herbs have been identified as substrates, inhibitors, and/or inducers of various CYP enzymes. For example, St. John's wort is a potent inducer of CYP3A4, which is mediated by activating the orphan pregnane X receptor. It also contains ingredients that inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Many other common medicinal herbs also exhibited inducing or inhibiting effects on the CYP system, with the latter being competitive, noncompetitive, or mechanism-based. It appears that the regulation of CYPs by herbal products is complex, depending on the herb type, their administration dose and route, the target organ and species. Due to the difficulties in identifying the active constituents responsible for the modulation of CYP enzymes, prediction of herb -drug metabolic interactions is difficult. However, herb-CYP interactions may have important clinical and toxicological consequences. For example, induction of CYP3A4 by St. John's wort may partly provide an explanation for the enhanced plasma clearance of a number of drugs, such as cyclosporine and innadivir, which are known substrates of CYP3A4, although other mechanisms including modulation of gastric absorption and drug transporters cannot be ruled out. In contrast, many organosulfur compounds, such as diallyl sulfide from garlic, are potent inhibitors of CYP2E1; this may provide an explanation for garlic's chemoproventive effects, as many mutagens require activation by CYP2E1. Therefore, known or potential herb -CYP interactions exist, and further studies on their clinical and toxicological roles are warranted. Given that increasing numbers of people are exposed to a number of herbal preparations that contain many constituents with potential of CYP modulation, high-throughput screening assays should be developed to explore herb-CYP interactions.Key Words: Herb; Cytochrome P450; Drug interactions.Abbreviations: Ah, aryl hydrocarbon; AUC, the area of the plasma concentrationtime curve; B[a]P, benzo[a]pyrene; C max , the maximum plasma concentration; CL int , intrinsic clearance; CYP, cytochrome P450; DAD, diallyl disulfide; DAS, diallyl sulfide; DASO, diallyl sulfoxide; DASO 2 , diallyl sulfone; DPS, dipropyl sulfide; DPDS, dipropyl disulfide; K i , inhibition constant; K m , Michaelis -Menten constant; NADPH, nicotinamide adenine dinucleotide phosphate; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; N-PiP, N-nitrosopiperidine; PgP, P-glycoprotein; PhIP...

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Section: Zhou Et Al 58mentioning

confidence: 94%

“…Some alkaloids (e.g., rutaecarpine, evodiamine, and dehydroevodiamine) isolated from Evodia rutaecarpa inhibited 7-methoxyresorufin O-demethylase and 7-ethoxyresorufin O-deethylase (both are CYP1A) activities in mouse liver microsomes (Ueng et al, 2002). Rutaecarpine (Fig.…”

Section: J Alkaloidsmentioning

confidence: 99%

Interactions of Herbs with Cytochrome P450

Zhou

Gao²,

Jiang

et al. 2003

Drug Metabolism Reviews

358

207

View full text Add to dashboard Cite

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“…Microsomal cytochrome P450 (P450)-dependent monooxygenase plays a major role in the oxidative metabolism of xenobiotics including drugs and natural products (Guengerich, 1995;Hasler et al, 1999). Our previous reports demonstrated that rutaecarpine was a CYP1A2-selective inhibitor in human liver microsomes (Ueng et al, 2002b). Rutaecarpine was metabolized by rat liver microsomal enzymes to form 10-, 11-, 12-, and 3-hydroxyrutaecarpine (Ueng et al, 2005).…”

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confidence: 99%

Oxidative Metabolism of the Alkaloid Rutaecarpine by Human Cytochrome P450

Ueng

Don²,

Jan³

et al. 2006

Drug Metab Dispos

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ABSTRACT: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 ␣-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 concen- Rutaecarpine is a main quinazolinocarboline alkaloid isolated from Evodia rutaecarpa (Wu-chu-yu), which has been used as a herbal medicine for the treatment of gastrointestinal disorder and headache (Liao et al., 1981;Tang and Eisenbrand, 1992). The remedy containing E. rutaecarpa is generally taken orally. The estimated dosage of rutaecarpine from ingestion of Wu-chu-yu tang, a remedy containing E. rutaecarpa, is approximately 19 mg/day (Ueng et al., 2002a). Rutaecarpine has a variety of pharmacological actions including antithrombotic, antianoxic, hypotensive, and vasorelaxant effects (Sheu, 1999). Microsomal cytochrome P450 (P450)-dependent monooxygenase plays a major role in the oxidative metabolism of xenobiotics including drugs and natural products (Guengerich, 1995;Hasler et al., 1999). Our previous reports demonstrated that rutaecarpine was a CYP1A2-selective inhibitor in human liver microsomes (Ueng et al., 2002b). Rutaecarpine was metabolized by rat liver microsomal enzymes to form 10-, 11-, 12-, and 3-hydroxyrutaecarpine (Ueng et al., 2005). Lee et al. (2004) reported that the formation rate of total rat rutaecarpine metabolites was stimulated by P450 inducers, 3-methylcholanthrene and phenobarbital, but not by acetone and dexamethasone. 3-Methylcholanthrene, phenobarbital, acetone, and dexamethasone are inducers of CYP1A, CYP2B, CYP2E1, and CYP3A, respectively, in rats (Waxman and Azaroff, 1992;Waxman, 1999). These results suggested that CYP1A and CYP2B played main roles in rat rutaecarpine metabolism. However, the main human P450 forms catalyzing rutaecarpine hydroxylations were not identified and the quantification and kinetic analyses were not reported.In human liver, CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 are the main P450 forms responsible for drug oxidation (Guengerich, 1995). CYP1A2, CYP2C, CYP2D6, CYP2E1, and CYP3A constitute approximately 13%, 18%, 2%, 7%, and 29% of the total P450 content, respectively (Shimada et al., 1994). CYP2C9 represents about half to 75% of total CYP2C (Lasker et al., 1998). CYP3A4 is the most abundant P450 form in human liver samples. CYP1A1 and CYP1B1 are expressed in low levels in human liver, but are inducible in the liver and play import...

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“…In addition, Fructus evodiae (fruit of E. rutaecarpa) is also used for the treatment of headache, thoracicoabdominal pain, vomiting, colds, and reduced blood circulation (Fei et al, 2003). Pharmacological studies indicate that Rut has various bioactivities, such as causing vasodilatation by mechanisms of an endothelium-dependent manner coupled with the synthesis or release of nitric oxide (Wang et al, 1996), inhibiting vasoconstriction induced by anaphylaxis (Yu et al, 2005), inducing positive inotropic and chronotropic actions (Kobayashi et al, 2001), protecting the myocardium mediated by calcitonin gene-related peptide (Hu et al, 2002;Yi et al, 2004), increasing intracellular Ca 2ϩ concentration in endothelium (Wang et al, 1996), suppressing platelet plug formation in mesenteric venules (Sheu et al, 2000), inhibiting prostaglandin production in RAW264.7 macrophages (Woo et al, 2001), relaxation of rabbit and human internal anal sphincter (Jiang et al, 2000), gastroprotective effect against injury induced by aspirin and stress (Wang et al, 2005), anti-Helicobacter pylori (Tominaga et al, 2002), blockade of delayed rectifier K ϩ current in NG108-15 neuronal cells (Wu et al, 2001), inhibiting cytochrome P450 in human liver microsomes (Ueng et al, 2002(Ueng et al, , 2006Iwata et al, 2005), and inhibition of COX-2 (Moon et al, 1999).…”

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confidence: 99%