Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

Department of Cell Biology and Genetics Faculty of Science Palacky University Olomouc Czech Republic

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Stejskalova L, Dvorak Z, Pavek P (2011) Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr Drug Metab 12: 198-212. doi:10.2174/138920011795016818. PubMed: 21395538. PubMed DOI

Abel J, Haarmann-Stemmann T (2010) An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391: 1235-1248. PubMed: 20868221. PubMed

Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H et al. (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 97: 779-782. doi:10.1073/pnas.97.2.779. PubMed: 10639156. PubMed DOI PMC

Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN et al. (1997) Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2: 645-654. PubMed: 9427285. PubMed

Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140: 173-179. doi:10.1006/taap.1996.0210. PubMed: 8806883. PubMed DOI

Park S, Dong B, Matsumura F (2007) Rapid activation of c-Src kinase by dioxin is mediated by the Cdc37-HSP90 complex as part of Ah receptor signaling in MCF10A cells. Biochemistry 46: 899-908. doi:10.1021/bi061925f. PubMed: 17223712. PubMed DOI

Pavek P, Dvorak Z (2008) Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues. Curr Drug Metab 9: 129-143. doi:10.2174/138920008783571774. PubMed: 18288955. PubMed DOI

Haarmann-Stemmann T, Bothe H, Abel J (2009) Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem Pharmacol 77: 508-520. doi:10.1016/j.bcp.2008.09.013. PubMed: 18848820. PubMed DOI

Fritsche E, Schäfer C, Calles C, Bernsmann T, Bernshausen T et al. (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A 104: 8851-8856. doi:10.1073/pnas.0701764104. PubMed: 17502624. PubMed DOI PMC

Haarmann-Stemmann T, Sendker J, Götz C, Krug N, Bothe H et al. (2010) Regulation of dioxin receptor function by different beta-carboline alkaloids. Arch Toxicol 84: 619-629. doi:10.1007/s00204-010-0548-2. PubMed: 20449727. PubMed DOI

Lee SK, Bista SR, Jeong H, Kim DH, Kang MJ et al. (2007) The effects of rutaecarpine on the pharmacokinetics of acetaminophen in rats. Arch Pharm Res 30: 1629-1634. doi:10.1007/BF02977334. PubMed: 18254252. PubMed DOI

Ueng YF, Tsai TH, Don MJ, Chen RM, Chen TL (2005) Alteration of the pharmacokinetics of theophylline by rutaecarpine, an alkaloid of the medicinal herb Evodia rutaecarpa, in rats. J Pharm Pharmacol 57: 227-232. doi:10.1211/0022357055489. PubMed: 15720787. PubMed DOI

Osher HL, Katz KH, Wagner DJ (1951) Khellin in the treatment of angina pectoris. N Engl J Med 244: 315-321. doi:10.1056/NEJM195103012440901. PubMed: 14806755. PubMed DOI

Scott RC, Iglauer A, Green RS, Kaufman JW, Berman B et al. (1951) Studies on the Effect of Oral and Parenteral Administration of Visammin (Khellin) in Patients with Angina Pectoris. Circulation 3: 80-88. doi:10.1161/01.CIR.3.1.80. PubMed: 14792730. PubMed DOI

Duarte J, Pérez-Vizcaíno F, Torres AI, Zarzuelo A, Jiménez J et al. (1995) Vasodilator effects of visnagin in isolated rat vascular smooth muscle. Eur J Pharmacol 286: 115-122. doi:10.1016/0014-2999(95)00418-K. PubMed: 8605947. PubMed DOI

Rauwald HW, Brehm O, Odenthal KP (1994) The involvement of a Ca2+ channel blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta Med 60: 101-105. doi:10.1055/s-2006-959426. PubMed: 8202556. PubMed DOI

Lee JK, Jung JS, Park SH, Park SH, Sim YB et al. (2010) Anti-inflammatory effect of visnagin in lipopolysaccharide-stimulated BV-2 microglial cells. Arch Pharm Res 33: 1843-1850. doi:10.1007/s12272-010-1117-1. PubMed: 21116788. PubMed DOI

Fabricant DS, Farnsworth NR (2001) The value of plants used in traditional medicine for drug discovery. Environ Health Perspect 109 Suppl 1: 69-75 PubMed

Abu-Hashem AA, Youssef MM (2011) Synthesis of new visnagen and khellin furochromone pyrimidine derivatives and their anti-inflammatory and analgesic activity. Molecules 16: 1956-1972. doi:10.3390/molecules16031956. PubMed: 21358587. PubMed DOI PMC

Atta SM, Farrag DS, Sweed AM, Abdel-Rahman AH (2010) Preparation of new polycyclic compounds derived from benzofurans and furochromones. An approach to novel 1,2,3-thia-, and selena-diazolofurochromones of anticipated antitumor activities. Eur J Med Chem 45: 4920-4927. PubMed

Ragab FA, El-Sayed NA, Eissa AA, Kerdawy El (2010) Synthesis and anticonvulsant activity of certain substituted furochromone, benzofuran and flavone derivatives. Chem Pharm Bull (Tokyo) 58: 1148-1156. doi:10.1248/cpb.58.1148. PubMed: 20823592. PubMed DOI

Vanachayangkul P, Chow N, Khan SR, Butterweck V (2011) Prevention of renal crystal deposition by an extract of Ammi visnaga L. and its constituents khellin and visnagin in hyperoxaluric rats. Urol Res 39: 189-195. PubMed PMC

de Leeuw J, Assen YJ, van der Beek N, Bjerring P, Martino Neumann HA (2011) Treatment of vitiligo with khellin liposomes, ultraviolet light and blister roof transplantation. J Eur Acad Dermatol Venereol 25: 74-81. doi:10.1111/j.1468-3083.2010.03701.x. PubMed: 20477914. PubMed DOI

Morliere P, Hönigsmann H, Averbeck D, Dardalhon M, Hüppe G et al. (1988) Phototherapeutic, photobiologic, and photosensitizing properties of khellin. J Invest Dermatol 90: 720-724. doi:10.1111/1523-1747.ep13083852. PubMed: 3283251. PubMed DOI

Pandini A, Denison MS, Song Y, Soshilov AA, Bonati L (2007) Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis. Biochemistry 46: 696-708. doi:10.1021/bi061460t. PubMed: 17223691. PubMed DOI PMC

Baumgart A, Schmidt M, Schmitz HJ, Schrenk D (2005) Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes. Biochem Pharmacol 69: 657-667. doi:10.1016/j.bcp.2004.11.017. PubMed: 15670584. PubMed DOI

Luecke S, Backlund M, Jux B, Esser C, Krutmann J et al. (2010) The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis. Pigment Cell. Melanoma Res 23: 828-833. PubMed

Jux B, Kadow S, Luecke S, Rannug A, Krutmann J et al. (2011) The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning. J Invest Dermatol 131: 203-210. doi:10.1038/jid.2010.269. PubMed: 20861855. PubMed DOI

Novotna A, Pavek P, Dvorak Z (2011) Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: construction and characterization. Environ Sci Technol 45: 10133-10139. doi:10.1021/es2029334. PubMed: 22017252. PubMed DOI

Dvorak Z, Vrzal R, Henklova P, Jancova P, Anzenbacherova E et al. (2008) JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes. Biochem Pharmacol 75: 580-588. doi:10.1016/j.bcp.2007.09.013. PubMed: 17959153. PubMed DOI

Fritsche E, Cline JE, Nguyen NH, Scanlan TS, Abel J (2005) Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect 113: 871-876. doi:10.1289/ehp.7793. PubMed: 16002375. PubMed DOI PMC

Fernández-Soria V, Lleonart ME, Diaz-Fuertes M, Villuendas R, Sánchez-Prieto R et al. (2006) Adenovirus E1A orchestrates the urokinase-plasminogen activator system and upregulates PAI-2 expression, supporting a tumor suppressor effect. Int J Oncol 28: 143-148. PubMed: 16327990. PubMed

Hasebe Y, Egawa K, Yamazaki Y, Kunimoto S, Hirai Y et al. (2003) Specific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids. Biol Pharm Bull 26: 1379-1383. doi:10.1248/bpb.26.1379. PubMed: 14519939. PubMed DOI

Seidel SD, Li V, Winter GM, Rogers WJ, Martinez EI et al. (2000) Ah receptor-based chemical screening bioassays: application and limitations for the detection of Ah receptor agonists. Toxicol Sci 55: 107-115. doi:10.1093/toxsci/55.1.107. PubMed: 10788565. PubMed DOI

Chao HR, Wang YF, Chen HT, Ko YC, Chang EE et al. (2007) Differential effect of arecoline on the endogenous dioxin-responsive cytochrome P450 1A1 and on a stably transfected dioxin-responsive element-driven reporter in human hepatoma cells. J Hazard Mater 149: 234-237. doi:10.1016/j.jhazmat.2007.07.022. PubMed: 17707585. PubMed DOI

Lu YF, Santostefano M, Cunningham BD, Threadgill MD, Safe S (1995) Identification of 3'-methoxy-4'-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells. Arch Biochem Biophys 316: 470-477. doi:10.1006/abbi.1995.1062. PubMed: 7840652. PubMed DOI

Schimmer O, Rauch P (1998) Inhibition of metabolic activation of the promutagens, benzo[a]pyrene, 2-aminofluorene and 2-aminoanthracene by furanochromones in Salmonella typhimurium. Mutagenesis 13: 385-389. doi:10.1093/mutage/13.4.385. PubMed: 9717176. PubMed DOI

Edenharder R, Speth C, Decker M, Kolodziej H, Kayser O et al. (1995) Inhibition of mutagenesis of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by coumarins and furanocoumarins, chromanones and furanochromanones. Mutat Res 345: 57-71. doi:10.1016/0165-1218(95)90070-5. PubMed: 8524356. PubMed DOI

Grossman SJ, Herold EG, Drey JM, Alberts DW, Umbenhauer DR et al. (1993) CYP1A1 specificity of Verlukast epoxidation in mice, rats, rhesus monkeys, and humans. Drug Metab Dispos 21: 1029-1036. PubMed: 7905381. PubMed

Aitchison KJ, Jann MW, Zhao JH, Sakai T, Zaher H et al. (2000) Clozapine pharmacokinetics and pharmacodynamics studied with Cyp1A2-null mice. J Psychopharmacol 14: 353-359. doi:10.1177/026988110001400403. PubMed: 11198052. PubMed DOI

Fuhr U, Woodcock BG, Siewert M (1992) Verapamil and drug metabolism by the cytochrome P450 isoform CYP1A2. Eur J Clin Pharmacol 42: 463-464. PubMed: 1516612. PubMed

Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ et al. (1996) 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA 93: 9776-9781. doi:10.1073/pnas.93.18.9776. PubMed: 8790407. PubMed DOI PMC

Ide F, Suka N, Kitada M, Sakashita H, Kusama K et al. (2004) Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor. Cancer Lett 214: 35-41. doi:10.1016/j.canlet.2004.04.014. PubMed: 15331171. PubMed DOI

Modi BG, Neustadter J, Binda E, Lewis J, Filler RB et al. (2012) Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. Science 335: 104-108. doi:10.1126/science.1211600. PubMed: 22223807. PubMed DOI PMC

Baba T, Mimura J, Gradin K, Kuroiwa A, Watanabe T et al. (2001) Structure and expression of the Ah receptor repressor gene. J Biol Chem 276: 33101-33110. doi:10.1074/jbc.M011497200. PubMed: 11423533. PubMed DOI

Haarmann-Stemmann T, Bothe H, Kohli A, Sydlik U, Abel J et al. (2007) Analysis of the transcriptional regulation and molecular function of the aryl hydrocarbon receptor repressor in human cell lines. Drug Metab Dispos 35: 2262-2269. doi:10.1124/dmd.107.016253. PubMed: 17890447. PubMed DOI

Haarmann-Stemmann T, Abel J (2006) The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function. Biol Chem 387: 1195-1199. PubMed: 16972786. PubMed

Zudaire E, Cuesta N, Murty V, Woodson K, Adams L et al. (2008) The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J Clin Invest 118: 640-650. PubMed: 18172554. PubMed PMC

Croucher DR, Saunders DN, Lobov S, Ranson M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8: 535-545. doi:10.1038/nrc2400. PubMed: 18548086. PubMed DOI

Sutter TR, Guzman K, Dold KM, Greenlee WF (1991) Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta. Science 254: 415-418. doi:10.1126/science.1925598. PubMed: 1925598. PubMed DOI

Rapisarda A, Melillo G (2012) Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv Cancer Res 114: 237-267. PubMed: 22588059. PubMed

Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438: 937-945. doi:10.1038/nature04479. PubMed: 16355211. PubMed DOI

Dong B, Matsumura F (2008) Roles of cytosolic phospholipase A2 and Src kinase in the early action of 2,3,7,8-tetrachlorodibenzo-p-dioxin through a nongenomic pathway in MCF10A cells. Mol Pharmacol 74: 255-263. doi:10.1124/mol.107.044669. PubMed: 18388244. PubMed DOI

Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM (2004) The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 199: 193-209. doi:10.1016/j.taap.2004.01.010. PubMed: 15364537. PubMed DOI

Ortel B, Tanew A, Hönigsmann H (1988) Treatment of vitiligo with khellin and ultraviolet A. J Am Acad Dermatol 18: 693-701. doi:10.1016/S0190-9622(88)70092-4. PubMed: 3270995. PubMed DOI

Hasa D, Perissutti B, Dall’acqua S, Chierotti MR, Gobetto R et al. (2012) Rationale of using Vinca minor Linne dry extract phytocomplex as a vincamine’s oral bioavailability enhancer. Eur J Pharm Biopharm, 84: 138–44. PubMed: 23238273. PubMed

Duschet P, Schwarz T, Pusch M, Gschnait F (1989) Marked increase of liver transaminases after khellin and UVA therapy. J Am Acad Dermatol 21: 592-594. doi:10.1016/S0190-9622(89)80248-8. PubMed: 2778124. PubMed DOI

Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines