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Planta Med 2014; 80(13): 1097-1106
DOI: 10.1055/s-0034-1383000
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Inhibition of Cytochrome P450 2C9 Expression and Activity In Vitro by Allyl Isothiocyanate

Yun-Ping Lim
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
2   Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung, Taiwan, ROC
,
Wei-Cheng Chen
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
3   Department of Pharmacy, National Cheng Kung University Hospital Dou-Liou Branch, Yunlin, Taiwan, ROC
,
Ching-Hao Cheng
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
4   Department of Pharmacy, Changhua Show Chwan Memorial Hospital, Changhua, Taiwan, ROC
,
Wei-Chih Ma
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
,
Yu-Hsien Lin
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
,
Cing-Yu Chen
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
,
Dong-Zong Hung
1   Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
2   Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung, Taiwan, ROC
,
Jih-Jung Chen
5   Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, Taiwan, ROC
,
Tsuyoshi Yokoi
6   Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
,
Miki Nakajima
6   Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
,
Chao-Jung Chen
7   Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan, ROC
8   Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
› Author Affiliations
Further Information

Publication History

received 27 March 2014
revised 06 June 2014

accepted 21 July 2014

Publication Date:
08 September 2014 (online)

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Inhibition of Cytochrome P450 2C9 Expression and Activity In Vitro by Allyl IsothiocyanatePlanta Med 2014; 80(14): 1247-1247
DOI: 10.1055/s-0034-1383128

Abstract

The growing interest in the use of natural herbal products and dietary supplements to treat and prevent diseases raises the question of medicinal drug safety. Allyl isothiocyanate, a hydrolysis product of a glucosinolate, sinigrin, has multiple beneficial properties, and based on this fact, allyl isothiocyanate-containing dietary supplements have been developed. To date, no studies of the effects of this compound on the cytochrome P450 2C9 have been reported. In this study, we found that allyl isothiocyanate reduced catalytic activity, messenger ribonucleic acid, and protein expression of cytochrome P450 2C9 in HepaRG cells. An investigation of the transcriptional activity of the pregnane X receptor and the constitutive androstane receptor revealed that allyl isothiocyanate disrupted the transcriptional coregulation effects of the pregnane X receptor/constitutive androstane receptor with several important coregulators and interfered with the assembly of transcriptional complexes of the cytochrome P450 2C9 pregnane X receptor/constitutive androstane receptor-response element. The decrease of cytochrome P450 2C9 expression and activity mediated by allyl isothiocyanate suggested that this agent could alter the metabolism of drugs metabolized by cytochrome P450 2C9. This may cause food/dietary supplement-drug interactions or alter the therapeutic effects, and even the toxicity of drugs coadministered with allyl isothiocyanate. Since the consumption of allyl isothiocyanate-containing food/dietary supplements continues to increase, it is important to predict and ultimately avoid interactions with concomitant drugs. It is required that these possible pharmacokinetic interactions be characterized and the recommendations available to patients and healthcare professionals be improved.

Key words

allyl isothiocyanate - pregnane X receptor - constitutive androstane receptor - cytochrome P450 2C9 - food/dietary supplement-drug interaction
 

  • References

  • 1 Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200-1205
    Google Scholar
  • 2 Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289: 1652-1658
    CrossrefPubMedGoogle Scholar
  • 3 Rodrigues M, Alves G, Falcão A. Investigating herb-drug interactions: the effect of Citrus aurantium fruit extract on the pharmacokinetics of amiodarone in rats. Food Chem Toxicol 2013; 60: 153-159
    CrossrefPubMedGoogle Scholar
  • 4 Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach SR, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol 2003; 43: 443-469
    CrossrefPubMedGoogle Scholar
  • 5 Nelson DR. Cytochrome P450 and the individuality of species. Arch Biochem Biophys 1999; 369: 1-10
    CrossrefPubMedGoogle Scholar
  • 6 Goldstein JA, de Morais SM. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4: 285-299
    CrossrefPubMedGoogle Scholar
  • 7 Miners JO, Birkett DJ. Cytochrome P450 2C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525-538
    CrossrefPubMedGoogle Scholar
  • 8 Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349-355
    CrossrefPubMedGoogle Scholar
  • 9 Chen Y, Ferguson SS, Negishi M, Goldstein JA. Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther 2004; 308: 495-501
    PubMedGoogle Scholar
  • 10 Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1975; 9: 219-227
    CrossrefPubMedGoogle Scholar
  • 11 Kay L, Kampmann JP, Svendsen TL, Vergman B, Hansen JE, Skovsted L, Kristensen M. Influence of rifampicin and isoniazid on the kinetics of phenytoin. Br J Clin Pharmacol 1985; 20: 323-326
    CrossrefPubMedGoogle Scholar
  • 12 Heimark LD, Gibaldi M, Trager WF, OʼReilly RA, Goulart DA. The mechanism of the warfarin-rifampin drug interaction in humans. Clin Pharmacol Ther 1987; 42: 388-394
    CrossrefPubMedGoogle Scholar
  • 13 Williamson KM, Patterson JH, McQueen RH, Adams jr. KF, Pieper JA. Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998; 63: 316-323
    CrossrefPubMedGoogle Scholar
  • 14 Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide. Clin Pharmacol Ther 2001; 69: 400-406
    CrossrefPubMedGoogle Scholar
  • 15 Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo . Clin Pharmacol Ther 2004; 75: 89-100
    CrossrefPubMedGoogle Scholar
  • 16 Al-Dosari MS, Knapp JE, Liu D. Activation of human CYP2C9 promoter and regulation by CAR and PXR in mouse liver. Mol Pharm 2006; 3: 322-328
    CrossrefPubMedGoogle Scholar
  • 17 Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998; 92: 73-82
    CrossrefPubMedGoogle Scholar
  • 18 Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol 2007; 72: 592-603
    CrossrefPubMedGoogle Scholar
  • 19 Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA. Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol 2002; 62: 737-746
    CrossrefPubMedGoogle Scholar
  • 20 EFSA. Scientific opinion on the safety of allyl isothiocyanate for the proposed uses as a food additive. EFSA Journal 2010; 8: 1943
    PubMedGoogle Scholar
  • 21 Shin IS, Masuda H, Naohide K. Bactericidal activity of wasabi (Wasabia japonica) against Helicobacter pylori . Int J Food Microbiol 2004; 94: 255-261
    CrossrefPubMedGoogle Scholar
  • 22 Wagner AE, Boesch-Saadatmandi C, Dose J, Schultheiss G, Rimbach G. Anti-inflammatory potential of allyl-isothiocyanate–role of Nrf2, NF-κB and microRNA-155. J Cell Mol Med 2012; 16: 836-843
    CrossrefPubMedGoogle Scholar
  • 23 Xiao D, Srivastava SK, Lew KL, Zeng Y, Hershberger P, Johnson CS, Trump DL, Singh SV. Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis. Carcinogenesis 2003; 24: 891-897
    CrossrefPubMedGoogle Scholar
  • 24 Ye L, Zhang Y. Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes. Carcinogenesis 2001; 22: 1987-1992
    CrossrefPubMedGoogle Scholar
  • 25 Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA. Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology 2011; 285: 18-24
    CrossrefPubMedGoogle Scholar
  • 26 Chen T, Tompkins LM, Li L, Li H, Kim G, Zheng Y, Wang H. A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3. J Pharmacol Exp Ther 2010; 332: 106-115
    CrossrefPubMedGoogle Scholar
  • 27 Gerbal-Chaloin S, Daujat M, Pascussi JM, Pichard-Garcia L, Vilarem MJ, Maurel P. Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. J Biol Chem 2002; 277: 209-217
    CrossrefPubMedGoogle Scholar
  • 28 Kirby BJ, Unadkat JD. Grapefruit juice, a glass full of drug interactions?. Clin Pharmacol Ther 2007; 81: 631-633
    CrossrefPubMedGoogle Scholar
  • 29 Molden E, Spigset O. Fruit and berries–interactions with drugs. Tidsskr Nor Laegeforen 2007; 127: 3218-3220
    PubMedGoogle Scholar
  • 30 Bollard M, Stribbling S, Mitchell S, Caldwell J. The disposition of allyl isothiocyanate in the rat and mouse. Food Chem Toxicol 1997; 35: 933-943
    CrossrefPubMedGoogle Scholar
  • 31 Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2005; 59: 425-432
    CrossrefPubMedGoogle Scholar
  • 32 Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ. Effects of St Johnʼs wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol 2008; 153: 1579-1586
    PubMedGoogle Scholar
  • 33 Srinivas NR. Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence. Eur J Drug Metab Pharmacokinet 2013; 38: 223-229
    CrossrefPubMedGoogle Scholar
  • 34 Auerbach SS, Ramsden R, Stoner MA, Verlinde C, Hassett C, Omiecinski CJ. Alternatively spliced isoforms of the human constitutive androstane receptor. Nucleic Acids Res 2003; 31: 3194-3207
    CrossrefPubMedGoogle Scholar
  • 35 Yu C, Chai X, Yu L, Chen S, Zeng S. Identification of novel pregnane X receptor activators from traditional Chinese medicines. J Ethnopharmacol 2011; 136: 137-143
    CrossrefPubMedGoogle Scholar
  • 36 Li L, Stanton JD, Tolson AH, Luo Y, Wang H. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharm Res 2009; 26: 872-882
    CrossrefPubMedGoogle Scholar
  • 37 Aninat C, Piton A, Glaise D, Le Charpentier T, Langouët S, Morel F, Guguen-Guillouzo C, Guillouzo A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 2006; 34: 75-83
    PubMedGoogle Scholar
  • 38 Wilkening S, Stahl F, Bader A. Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos 2003; 31: 1035-1042
    CrossrefPubMedGoogle Scholar
  • 39 Lim YP, Ma CY, Liu CL, Lin YH, Hu ML, Chen JJ, Hung DZ, Hsieh WT, Huang JD. Sesamin: a naturally occurring lignan inhibits CYP3A4 by antagonizing the pregnane X receptor activation. Evid Based Complement Alternat Med 2012; 2012: 242810
    PubMedGoogle Scholar
  • 40 Itoh M, Nakajima M, Higashi E, Yoshida R, Nagata K, Yamazoe Y, Yokoi T. Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. J Pharmacol Exp Ther 2006; 319: 693-702
    CrossrefPubMedGoogle Scholar
  • 41 Wang H, Faucette S, Sueyoshi T, Moore R, Ferguson S, Negishi M, LeCluyse EL. A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem 2003; 278: 14146-14152
    CrossrefPubMedGoogle Scholar
  • 42 Lo WS, Lim YP, Chen CC, Hsu CC, Souček P, Yun CH, Xie W, Ueng YF. A dual function of the furanocoumarin chalepensin in inhibiting Cyp2a and inducing Cyp2b in mice: the protein stabilization and receptor-mediated activation. Arch Toxicol 2012; 86: 1927-1938
    CrossrefPubMedGoogle Scholar
  • 43 Zambon S, Fontana S, Kajbaf M. Evaluation of cytochrome P450 inhibition assays using human liver microsomes by a cassette analysis LC-MS/MS. Drug Metab Lett 2010; 4: 120-128
    CrossrefPubMedGoogle Scholar