Effective Cytochrome P450 (CYP) Inhibitors Isolated from Tarragon (Artemisia dracunculus)

Abstract

Two effective cytochrome P450 (CYP) inhibitors were isolated from tarragon, Artemisia dracunculus. Their structures were spectroscopically identified as 2E,4E-undeca-2,4-diene-8,10-diynoic acid isobutylamide (1) and 2E,4E-undeca-2,4-diene-8,10-diynoic acid piperidide (2). Both compounds had dose-dependent inhibitory effects on CYP3A4 activity with IC 50 values of 10:0 AE 1:3 M for compound 1 and 3:3 AE 0:2 M for compound 2, and exhibited mechanism-based inhibition. This is the first reported isolation of effective CYP inhibitors from tarragon (Artemisia dracunculus) purchased from a Japanese market.Key words: 2E,4E-undeca-2,4-diene-8,10-diynoic acid isobutylamide; 2E,4E-undeca-2,4-diene-8,10-diynoic acid piperidide; cytochrome P450 inhibitor; tarragon; Artemisia dracunculus Tarragon (estragon), Artemisia dracunculus, is a perennial herb with a long history of medicinal and culinary use.1) In particular, it is a crucial spice for French cuisine. The ethanolic extract of A. dracunculus has significantly decreased the blood glucose level and improved the insulin level in both genetic and chemical murine models of hyperglycemia.2,3) It had been demonstrated in Caco-2 cells that the extract also had potent inhibitory activity against allergen absorption. 4)Cytochrome P450 monooxygenases (CYPs), comprising a large and ubiquitous enzyme family, are hemecontaining mixed-function oxidases that play a key role in the hepatic metabolism of lipophilic endogenetic substrates such as hormones, and of ingested hydrophobic xenobiotics such as medicinal chemicals and natural products. CYPs generally convert a large number of exogenous compounds (toxic, carcinogenic, and most pharmaceutical agents) to less toxic compounds. CYP enzymes, including CYP3A4, CYP1A2, CYP2C9, and CYP2D6, are mainly expressed in the human liver and gastrointestinal tract and metabolize many pharmacologic agents and chemicals.5) The co-administration of foods that contain CYP inhibitors and drugs often causes adverse effects (food-drug interaction). [6][7][8] The extrahepatic expression of CYPs has also been established. Such CYP families as CYPs 1, 2 and 3 are involved in the metabolism of carcinogenic, pro-carcinogenic, and chemotherapeutic substances, and are found in several extrahepatic tissues. CYPs 17 and 19 are involved in the metabolism required for respectively producing androgens and estrogens, and are located in the testes, ovaries, and adrenals.9) Food materials with selective inhibitors against specific CYPs are therefore potential candidates for cancer prevention strategies.To elucidate the food factors in aromatic and medicinal plants that either inhibit or exploit CYP enzymes for the treatment of cancer, we evaluated the dry material of tarragon, A. dracunculus, purchased in a Japanese market (S&B Foods, Tokyo, Japan) for the compounds active against CYPs. We report here the isolation, identification, and inhibitory activities of two active compounds, 1 and 2, against CYPs 1A2, 2C9, 2D6, and 3A4.The dry material of A. dracunculus (200 g),...

The chemistry and pharmacology of alkaloids and allied nitrogen compounds fromArtemisiaspecies: A review

“…Brahmi et al () tested Neopellitorine A ( 39 ) and Neopellitorine B ( 40 ) against P450 (CYP) inhibition where both compounds 39 and 40 exhibited mechanism‐based and dose‐dependent inhibition of CYP3A4 activity with IC 50 10.0 ± 1.3 and 3.3 ± 0.2 μM, respectively. Inhibition of CYP450 is pharmacologically very important as it is a major factor interacting with a drug after its administration altering their pharmacokinetics and response.…”

Inhibitory Effects of Metabolites Isolated from Artemisia dracunculus L. Against the Human Carbonic Anhydrase I (hCA I) and II (hCA II)

“…In addition, some regional varieties of tarragon are distinguished by their essential oil content [1,15,16]. The principal seconder metabolites of A. dracunculus L. are pyhtoalexins, coumarins, chromones, phenylpropanoids, phenylpropenes, chalcones, alkamides, polyphenolics, acetylenes, monoterpenes alkamides, flavonoids and sesquiterpene lactones [17][18][19][20][21][22][23]. The marker compound in the composition of A. dracunculus L. leaves is reported as herniarin [24].…”

Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine

“…Many studies have reported the MBI of human CYPs by constituents isolated from traditional herbal medicines [27,28,29]. For the TDI assessment with H. helix extracts, IC 50 shifts were calculated by comparing IC 50 vales from the co-incubation assay to the pre-incubation assay [17], which showed positive results (≥1.5) for CYP2C8 and CYP2C19.…”