Tags

Type your tag names separated by a space and hit enter

Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract.
Drug Metab Pharmacokinet. 2005 Feb; 20(1):34-45.DM

Abstract

Evodia fruit (Evodiae Fructus) is used as a herbal medicine prepared from the matured fruit of the Evodia rutaecarpa Bentham or Evodia officinalis Dode, of the Rutaceae plant family. An extract of Evodia fruit in the presence of NADPH was shown to inhibit human liver microsomal erythromycin N-demethylation activity, mediated by cytochrome P450 3A4 (CYP3A4), in a preincubation-time dependent manner. The present study was conducted to identify components of Evodia fruit extract having preincubation-time dependent inhibitory effects on CYP3A4 by analyzing human liver microsomal erythromycin N-demethylation activity. Rutaecarpine, a major component of Evodia fruit, and limonin caused the most dramatic decrease in residual CYP3A4 activity (IC50 before and after 20 min preincubation with: rutaecarpine, >100 microM and 1.4 microM; limonin, 23.5 microM and 1.8 microM, respectively). Furthermore, rutaecarpine and limonin were identified as mechanism-based inhibitors of CYP3A4 from the following observations: 1) The inhibitory effects of rutaecarpine and limonin on CYP3A4 activity were dependent on the preincubation time, 2) The inhibition required NADPH, 3) The inhibition was depressed in the presence of the competitive CYP3A4 inhibitor, ketoconazole, 4) Dialysis resulted in no recovery of CYP3A4 activity. The kinetic parameters for inactivation k(inact) and K(I) were: 0.387 min-1 and 107.7 microM for rutaecarpine, 0.266 min-1 and 23.2 microM for limonin, respectively. These results indicate that rutaecarpine and limonin are mechanism-based inhibitors of CYP3A4.

Authors+Show Affiliations

Iwata H
Division of Natural Products Chemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Tezuka Y
No affiliation info available
Kadota S
No affiliation info available
Hiratsuka A
No affiliation info available
Watabe T
No affiliation info available

MeSH

AlkaloidsChromatography, High Pressure LiquidCytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InhibitorsEvodiaFruitHumansIndole AlkaloidsKineticsLimoninsMagnetic Resonance SpectroscopyMicrosomes, LiverPlant ExtractsQuinazolines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15770073

Citation

Iwata, Hiroshi, et al. "Mechanism-based Inactivation of Human Liver Microsomal CYP3A4 By Rutaecarpine and Limonin From Evodia Fruit Extract." Drug Metabolism and Pharmacokinetics, vol. 20, no. 1, 2005, pp. 34-45.
Iwata H, Tezuka Y, Kadota S, et al. Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract. Drug Metab Pharmacokinet. 2005;20(1):34-45.
Iwata, H., Tezuka, Y., Kadota, S., Hiratsuka, A., & Watabe, T. (2005). Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract. Drug Metabolism and Pharmacokinetics, 20(1), 34-45.
Iwata H, et al. Mechanism-based Inactivation of Human Liver Microsomal CYP3A4 By Rutaecarpine and Limonin From Evodia Fruit Extract. Drug Metab Pharmacokinet. 2005;20(1):34-45. PubMed PMID: 15770073.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract. AU - Iwata,Hiroshi, AU - Tezuka,Yasuhiro, AU - Kadota,Shigetoshi, AU - Hiratsuka,Akira, AU - Watabe,Tadashi, PY - 2005/3/17/pubmed PY - 2005/9/10/medline PY - 2005/3/17/entrez SP - 34 EP - 45 JF - Drug metabolism and pharmacokinetics JO - Drug Metab Pharmacokinet VL - 20 IS - 1 N2 - Evodia fruit (Evodiae Fructus) is used as a herbal medicine prepared from the matured fruit of the Evodia rutaecarpa Bentham or Evodia officinalis Dode, of the Rutaceae plant family. An extract of Evodia fruit in the presence of NADPH was shown to inhibit human liver microsomal erythromycin N-demethylation activity, mediated by cytochrome P450 3A4 (CYP3A4), in a preincubation-time dependent manner. The present study was conducted to identify components of Evodia fruit extract having preincubation-time dependent inhibitory effects on CYP3A4 by analyzing human liver microsomal erythromycin N-demethylation activity. Rutaecarpine, a major component of Evodia fruit, and limonin caused the most dramatic decrease in residual CYP3A4 activity (IC50 before and after 20 min preincubation with: rutaecarpine, >100 microM and 1.4 microM; limonin, 23.5 microM and 1.8 microM, respectively). Furthermore, rutaecarpine and limonin were identified as mechanism-based inhibitors of CYP3A4 from the following observations: 1) The inhibitory effects of rutaecarpine and limonin on CYP3A4 activity were dependent on the preincubation time, 2) The inhibition required NADPH, 3) The inhibition was depressed in the presence of the competitive CYP3A4 inhibitor, ketoconazole, 4) Dialysis resulted in no recovery of CYP3A4 activity. The kinetic parameters for inactivation k(inact) and K(I) were: 0.387 min-1 and 107.7 microM for rutaecarpine, 0.266 min-1 and 23.2 microM for limonin, respectively. These results indicate that rutaecarpine and limonin are mechanism-based inhibitors of CYP3A4. SN - 1347-4367 UR - https://www.unboundmedicine.com/medline/citation/15770073/Mechanism_based_inactivation_of_human_liver_microsomal_CYP3A4_by_rutaecarpine_and_limonin_from_Evodia_fruit_extract_ DB - PRIME DP - Unbound Medicine ER -