RSS-Feed abonnieren
DOI: 10.1055/s-2008-1081351
© Georg Thieme Verlag KG Stuttgart · New York
In Vitro Mechanism-Based Inactivation of Cytochrome P450 3A4 by a New Constituent of Cinnamomum burmani
Publikationsverlauf
Received: Februay 25, 2008
Revised: July 3, 2008
Accepted: July 7, 2008
Publikationsdatum:
09. September 2008 (online)
![](https://www.thieme-connect.de/media/plantamedica/200812/lookinside/thumbnails/10.1055-s-2008-1081351-1.jpg)
Abstract
Cytochrome P450 enzymes play an important role in drug metabolism. Various studies have reported the potential inhibition of these enzymes by natural compounds, leading to possible drug-herb interaction. One study reported that the MeOH extract of Cinnamomum burmani inhibited CYP3A4 in a mechanism-based mode. Further phytochemical investigation on this plant led to the isolation of 17 compounds including 2 new compounds: cinnamic aldehyde cyclic syringylglycerol 1,3-acetal (1) and 5′-hydroxy-5-hydroxymethyl-4′′,5′′-methylenedioxy-1,2,3,4-dibenzo-1,3,5-cycloheptatriene (2). The isolated constituents were tested for their preincubation time-dependent inhibition of CYP3A4 at 0 and 20 min. Only the new compound 2 showed an increase in the inhibitory activity to >50 % after 20-min preincubation. Further investigations of the inactivation by 2 displayed characteristics of a mechanism-based inactivator, with K I and k inact values of 7.7 μM and 0.04 min−1, respectively.
Key words
Cinnamomum burmani - Lauraceae - cytochrome P450 3A4 - CYP3A4 - mechanism-based inactivation
References
-
1 Clarke S E, Jones B C. Human cytochrome P450 and their role in metabolism-based drug-drug interactions. In: Rodrigues AD, editor
Drug-drug interactions . New York; Marcel Dekker Inc 2002: 55-88 - 2 Murray M. Mechanism of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr Drug Metab. 2000; 1 67-84
- 3 Guengerich F P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol. 2001; 14 611-50
- 4 Lin J H, Lu A YH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998; 35 361-90
- 5 Silverman R B. Mechanism-based enzyme inactivation: Chemistry and enzymology I. Florida; CRC Press 1988: 1-30
- 6 Izzo A A. Herb-drug interactions: an overview of the clinical evidence. Fundam Clin Pharmacol. 2004; 19 1-16
- 7 Tassaneeyakul W, Guo L, Fukuda K, Ohta T, Yamazoe Y. Inhibition selectivity of grapefruit juice components on human cytochromes P450. Arch Biochem Biophys. 2000; 378 356-63
- 8 Usia T, Watabe T, Kadota S, Tezuka Y. Metabolite-cytochrome P450 complex formation by methylenedioxyphenyl lignans of Piper cubeba: Mechanism-based inhibition. Life Sci. 2005; 76 2381-91
- 9 Subehan , Zaidi S HF, Kadota S, Tezuka Y. Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): Identification and characterization of a mechanism-based inactivator. Agric Food Chem. 2007; 55 10 162-7
- 10 Subehan , Usia T, Kadota S, Tezuka Y. Mechanism-based inhibition of human liver microsomal cytochrome P450 2D6 (CYP2D6) by alkamide of Piper nigrum. Planta Med. 2006; 72 527-32
- 11 Subehan , Usia T, Iwata H, Kadota S, Tezuka Y. Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants. J Ethnopharmacol. 2006; 105 449-55
- 12 PT Eisai Indonesia. Medicinal Herb Index in Indonesia. Jakarta; PT Eisai 1995: 10
-
13 Rodrigues F P. Measurement of human liver microsomal cytochrome P450 2D6 activity using [O-methyl-14C]-dextromethorphan as substrate. In: Johnson EF, Waterman MR, editors
Cytochrome P450 . New York; Academic Press 1996: 86-195 - 14 Iwata H, Tezuka Y, Usia T, Kadota S, Hiratsuka A, Watabe T. Inhibition of human liver microsomal CYP3A4 and CYP2D6 by extract from 78 herbal medicines. J Tradit Med. 2004; 21 42-50
- 15 Palamanda J R, Casciano C N, Norton L A, Clement R P, Favreu L V, Lin C C. et al . Mechanism-based inactivation of CYP2D6 by 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine. Drug Metab Dispos. 2001; 29 863-7
- 16 Pouchert C J, Behnke J. The Aldrich Library of 13C and 1H FTNMR spectra, 1st edition. USA: Aldrich Chemical Company. Inc.; 1993 392, 926, 1043, 1202, 1311
- 17 Ren X, Chen X, Peng K, Xie X, Xia Y, Pan X. First enantioselective synthesis of daphneticin and its regioisomer. Tetrahedron Asymm. 2002; 13 1799-804
- 18 Talapatra S K, Patra A, Talapatra B. Terpenoids and related compounds. Part XVII. Neutral constituents of Michelia lanuginose Well. Structures, absolute configuration and conformation of three new germacranolides. A novel rearrangement of lanuginolide. J Indian Chem Soc. 1978; 55 1152-60
- 19 Barakat H H, Nawwar M AM, Baddrus J, Linscheid M. Niloticol, a phenolic glyceride and two phenolic aldehydes from the roots of Tamarix nilotica. . Phytochemistry. 1987; 26 1837-8
- 20 Ishi H, Chen I S, Akaike M, Ishikawa T, Lu S T. Studies on the chemical constituents of rutaceous plants. LIX. The chemical constituents of Xanthoxylum nitidum (Roxb.) D.C. (Fagara nitida Roxb.) (1) Examination of the alkaloidal fraction of the bark. Yakugaku Zasshi. 1982; 102 182-95
- 21 Anjaneyulu A SR, Prakash C VS, Raju K VS, Mallavadhani U V. Isolation of new aromatic derivatives from a marine algal species Caulerpa racemosa. . J Nat Prod. 1992; 55 496-9
- 22 Abrams S R, Reaney M JT, Abrams G D, Mazurek T, Shaw A C, Gusta L V. Ratio of (S)- to (R)-abscisic acid from plant cell cultures supplied with racemic aba. Phytochemistry. 1989; 28 2885-9
- 23 Deyama T. The constituents of Eucommia elmoides Oliv. I. Isolation of (+)-medioresinol di-O-β-D-glucopyranoside. Chem Pharm Bull. 1983; 31 2993-7
- 24 Mukherjee R K, Fujimoto Y, Kakinuma K. 1-(Hydroxyfattyacyl)glycerols and two flavanols from Cinnamomum camphora. . Phytochemisty. 1994; 37 1641-3
- 25 von Moltke L L, Greenblatt D J, Duan S X, Harmatz J S, Shader R I. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J Clin Pharmacol. 1994; 34 1222-7
- 26 Labro R B, Thummel K E, Kunze K L, Podoll T, Trager W F, Kharasch E D. Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism. Drug Metab Dispos. 1995; 23 490-6
- 27 Hasegawa A, Yoshino M, Nakamura H, Ishii I, Watanabe T, Kiuchi M. et al . Identification of the inhibitory components in cinnamon – o-methoxycinnamaldehyde inhibits CYP1A2 and CYP2E1. Drug Metabol Pharmacokinet. 2002; 17 229-36
- 28 Devaraj H, Niranjali S, Raveendran M. Effect of food flavor cinnamaldehyde on liver microsomal cytochrome P-450 in rats. Bull Environ Contam Toxicol. 1992; 49 306-11
- 29 Raner G M, Chiang E W, Vaz A DN, Coon M J. Mechanism-based inactivation of cytochrome P450 2B4 by aldehydes: Relationship to aldehyde deformation via a peroxyhemiacetal intermediate. Biochemistry. 1997; 36 4895-902
- 30 Zhou S, Koh H L, Gao Y, Gong Z, Lee E JD. Herbal bioactivation: The good, the bad and the ugly. Life Sci. 2004; 74 935-68
- 31 Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract. Drug Metab Dispos. 2004; 32 1351-8
Dr. Yasuhiro Tezuka
Institute of Natural Medicine
University of Toyama
2630-Sugitani
Toyama 930–0194
Japan
Telefon: +81-76-434-7627
Fax: +81-76-434-5059
eMail: tezuka@inm.u-toyama.ac.jp