药学学报, 2016, 51(6): 860-865
引用本文:
贾永明, 刘志浩, 刘克辛. 白藜芦醇对药物转运体和代谢酶影响的研究进展[J]. 药学学报, 2016, 51(6): 860-865.
JIA Yong-ming, LIU Zhi-hao, LIU Ke-xin. Progress in regulation of drug transporters and metabolic enzymes by resveratrol[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 860-865.

白藜芦醇对药物转运体和代谢酶影响的研究进展
贾永明, 刘志浩, 刘克辛
大连医科大学药学院, 辽宁 大连 116044
摘要:
药物转运体和药物代谢酶是影响药物在体内处置的两个关键因素。白藜芦醇作为新兴的抗肿瘤药物与转运体和药物代谢酶的关系密切。众所周知,白藜芦醇能够直接激活或抑制诸多转运体的功能及调控多种转运体的表达。白藜芦醇同样能够抑制药物代谢酶细胞色素P450(CYP450)的功能及调控药物代谢酶表达。因此,当白藜芦醇与其他药物合用时,可能发生药物相互作用(drug-drug interaction, DDI)。本文从药物转运体和代谢酶在体内的分布、白藜芦醇对转运体及代谢酶的影响及转运体和代谢酶介导白藜芦醇与其他药物发生相互作用等方面进行综述。
关键词:    转运体      代谢酶      白藜芦醇      药物相互作用     
Progress in regulation of drug transporters and metabolic enzymes by resveratrol
JIA Yong-ming, LIU Zhi-hao, LIU Ke-xin
College of Pharmacy, Dalian Medical University, Dalian 116044, China
Abstract:
Drug transporters and metabolic enzymes are two major factors in the regulation of disposition of drug in the body. Interestingly, resveratrol, as a new star of anticancer drug, has a close relationship with transporters and metabolic enzymes. It is known that resveratrol can activate or inhibit the function of several transporters directly. Furthermore, the expression of several transporters was changed. Meanwhile, resveratrol is able to inhibit the function of metabolic enzymes (cytochrome P450, CYP450) and regulate the expression of metabolic enzymes. For this reason, when resveratrol is administrated in combination with other drugs, drug-drug interaction (DDI) should be considered. In this review, we summarize the distribution of transporters and metabolic enzymes in the body, the effect of resveratrol on transporters and metabolic enzymes as well as the drug-resveratrol interaction mediated by transporters and metabolic enzymes.
Key words:    transporter    metabolic enzyme    resveratrol    drug-drug interaction   
收稿日期: 2015-10-26
DOI: 10.16438/j.0513-4870.2015-0976
基金项目: 国家自然科学基金资助项目(81273580,81473280).
通讯作者: 刘克辛,Tel/Fax:86-411-86110407,E-mail:kexinliu@dlmedu.edu.cn
Email: kexinliu@dlmedu.edu.cn
相关功能
PDF(354KB) Free
打印本文
0
作者相关文章
贾永明  在本刊中的所有文章
刘志浩  在本刊中的所有文章
刘克辛  在本刊中的所有文章

参考文献:
[1] Maier-Salamon A, Bohmdorfer M, Thalhammer T, et al. Hepatic glucuronidation of resveratrol:interspecies comparison of enzyme kinetic profiles in human, mouse, rat, and dog[J]. Drug Metab Pharmacokinet, 2011, 26:364-373.
[2] Li JP. Resveratrol caused apoptosis in QGY-7701 cells[J]. Eur Rev Med Pharmacol Sci, 2015, 19:3303-3308.
[3] Trung LQ, Espinoza JL, An DT, et al. Resveratrol selectively induces apoptosis in malignant cells with the JAK2V617F mutation by inhibiting the JAK2 pathway[J]. Mol Nutr Food Res, 2015, 59:2143-2154.
[4] Choi JS, Choi BC, Kang KW. Effect of resveratrol on the pharmacokinetics of oral and intravenous nicardipine in rats:possible role of P-glycoprotein inhibition by resveratrol[J]. Pharmazie, 2009, 64:49-52.
[5] Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane transporters in drug development[J]. Nat Rev Drug Discov, 2010, 9:215-236.
[6] Wang L, Liu KX. Alteration of related transporters and its application significance in common intestinal disease, liver disease, renal disease and diabetes[J]. Acta Pharm Sin (药学学报), 2015, 50:127-132.
[7] Shitara Y, Sato H, Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs[J]. Annu Rev Pharmacol Toxicol, 2005, 45:689-723.
[8] Liu Z, Wang C, Liu Q, et al. Uptake, transport and regulation of JBP485 by PEPT1 in vitro and in vivo[J]. Peptides, 2011, 32:747-754.
[9] Zhang J, Wang C, Liu Q, et al. Pharmacokinetic interaction between JBP485 and cephalexin in rats[J]. Drug Metab Dispos, 2010, 38:930-938.
[10] Wang L, Wang C, Peng J, et al. Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo[J]. Toxicol Appl Pharmacol, 2014, 277:146-154.
[11] Cheng X, Gu J, Klaassen CD. Adaptive hepatic and intestinal alterations in mice after deletion of NADPH-cytochrome P450 oxidoreductase (Cpr) in hepatocytes[J]. Drug Metab Dispos, 2014, 42:1826-1833.
[12] Liska DJ. The detoxification enzyme systems[J]. Altern Med Rev, 1998, 3:187-198.
[13] Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology[J]. J Clin Psychopharmacol, 2001, 21:500-515.
[14] Geillinger KE, Kipp AP, Schink K, et al. Nrf2 regulates the expression of the peptide transporter PEPT1 in the human colon carcinoma cell line Caco-2[J]. Biochim Biophys Acta, 2014, 1840:1747-1754.
[15] Jia Y, Liu Z, Huo X, et al. Enhancement effect of resveratrol on the intestinal absorption of bestatin by regulating PEPT1, MDR1 and MRP2 in vivo and in vitro[J]. Int J Pharm, 2015, 495:588-598.
[16] Cui Y, Konig J, Leier I, et al. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6[J]. J Biol Chem, 2001, 276:9626-9630.
[17] Kindla J, Muller F, Mieth M, et al. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport[J]. Drug Metab Dispos, 2011, 39:1047-1053.
[18] Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides[J]. Drug Metab Dispos, 2011, 39:920-926.
[19] Riha J, Brenner S, Bohmdorfer M, et al. Resveratrol and its major sulfated conjugates are substrates of organic anion transporting polypeptides (OATPs):impact on growth of ZR-75-1 breast cancer cells[J]. Mol Nutr Food Res, 2014, 58:1830-1842.
[20] Chothe PP, Swaan PW. Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)[J]. Biochem J, 2014, 459:301-312.
[21] Yerasi N, Vurimindi H, Devarakonda K. Frog intestinal perfusion to evaluate drug permeability:application to P-gp and CYP3A4 substrates[J]. Front Pharmacol, 2015, 6:141.
[22] Chen T, Wang C, Liu Q, et al. Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway[J]. Cancer Biol Ther, 2015, 16:106-114.
[23] Planas JM, Alfaras I, Colom H, et al. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters[J]. Arch Biochem Biophys, 2012, 527:67-73.
[24] Hong SP, Choi DH, Choi JS. Effects of resveratrol on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem, in rats[J]. Cardiovasc Ther, 2008, 26:269-275.
[25] Kim TH, Shin YJ, Won AJ, et al. Resveratrol enhances chemosensitivity of doxorubicin in multidrug-resistant human breast cancer cells via increased cellular influx of doxorubicin[J]. Biochim Biophys Acta, 2014, 1840:615-625.
[26] Wang L, Wang C, Jia Y, et al. Resveratrol increases anti-proliferative activity of bestatin through downregulating P-glycoprotein expression via inhibiting PI3K/Akt/mTOR pathway in K562/ADR cells[J]. J Cell Biochem, 2015. DOI:10.1002/jcb.25407.
[27] Kamisako T, Leier I, Cui Y, et al. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2[J]. Hepatology, 1999, 30:485-490.
[28] Masuda M, I'izuka Y, Yamazaki M, et al. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats[J]. Cancer Res, 1997, 57:3506-3510.
[29] Kweon SH, Song JH, Kim TS. Resveratrol-mediated reversal of doxorubicin resistance in acute myeloid leukemia cells via downregulation of MRP1 expression[J]. Biochem Biophys Res Commun, 2010, 395:104-110.
[30] Juan ME, Gonzalez-Pons E, Planas JM. Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats[J]. J Nutr, 2010, 140:489-495.
[31] Kim JH, Chen C, Tony Kong AN. Resveratrol inhibits genistein-induced multi-drug resistance protein 2(MRP2) expression in HepG2 cells[J]. Arch Biochem Biophys, 2011, 512:160-166.
[32] Wang T, Zhou ZX, Sun LX, et al. Resveratrol effectively attenuates alpha-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms[J]. Acta Pharmacol Sin, 2014, 35:1527-1536.
[33] van de Wetering K, Burkon A, Feddema W, et al. Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3(MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol[J]. Mol Pharmacol, 2009, 75:876-885.
[34] El-Sheikh AA, Morsy MA, Al-Taher AY. Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage[J]. Life Sci, 2014, 119:40-46.
[35] Jonker JW, Smit JW, Brinkhuis RF, et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan[J]. J Natl Cancer Inst, 2000, 92:1651-1656.
[36] Matsushima S, Maeda K, Kondo C, et al. Identification of the hepatic efflux transporters of organic anions using doubletransfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1(OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein[J]. J Pharmacol Exp Ther, 2005, 314:1059-1067.
[37] Ebert B, Seidel A, Lampen A. Phytochemicals induce breast cancer resistance protein in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate[J]. Toxicol Sci, 2007, 96:227-236.
[38] Wang C, Liu KX. The drug-drug interaction mediated by efflux transporters and CYP450 enzymes[J]. Acta Pharm Sin (药学学报), 2014, 49:590-595.
[39] Chow HH, Garland LL, Hsu CH, et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study[J]. Cancer Prev Res (Phila), 2010, 3:1168-1175.
[40] Regev-Shoshani G, Shoseyov O, Kerem Z. Influence of lipophilicity on the interactions of hydroxy stilbenes with cytochrome P4503A4[J]. Biochem Biophys Res Commun, 2004, 323:668-673.
[41] Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products[J]. Drug Metab Dispos, 2003, 31:533-539.
[42] Sergent T, Dupont I, Van der Heiden E, et al. CYP1A1 and CYP3A4 modulation by dietary flavonoids in human intestinal Caco-2 cells[J]. Toxicol Lett, 2009, 191:216-222.
[43] Yu C, Shin YG, Kosmeder JW, et al. Liquid chromatography/tandem mass spectrometric determination of inhibition of human cytochrome P450 isozymes by resveratrol and resveratrol-3-sulfate[J]. Rapid Commun Mass Spectrom, 2003, 17:307-313.
[44] Piver B, Berthou F, Dreano Y, et al. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components[J]. Toxicol Lett, 2001, 125:83-91.
[45] Gusman J, Malonne H, Atassi G. A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol[J]. Carcinogenesis, 2001, 22:1111-1117.
[46] Revel A, Raanani H, Younglai E, et al. Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene[J]. J Appl Toxicol, 2003, 23:255-261.
[47] McLaughlin LA, Dickmann LJ, Wolf CR, et al. Functional expression and comparative characterization of nine murine cytochromes P450 by fluorescent inhibition screening[J]. Drug Metab Dispos, 2008, 36:1322-1331.
[48] Mikstacka R, Gnojkowski J, Baer-Dubowska W. Effect of natural phenols on the catalytic activity of cytochrome P4502E1[J]. Acta Biochim Pol, 2002, 49:917-925.
[49] Lilja JJ, Kivistö KT, Backman JT, et al. Grapefruit juice substantially increases plasma concentrations of buspirone[J]. Clin Pharmacol Ther, 1998, 64:655-660.
相关文献:
1.杨波, 王静, 丛宇婷, 胡良海, 顾景凯.基于蛋白质组学的药物代谢酶与转运体定量分析研究进展[J]. 药学学报, 2015,50(6): 668-674
2.刘琦, 刘克辛.代谢酶和转运体介导的中药-西药相互作用的药动学机制研究进展[J]. 药学学报, 2015,50(4): 406-412
3.李聃, 盛莉, 李燕.药物转运体的研究方法[J]. 药学学报, 2014,49(7): 963-970
4.高纯颖,陈笑艳,钟大放.转运体在药物经肝脏清除过程中的作用[J]. 药学学报, 2012,47(5): 565-572