基于乳腺癌耐药蛋白介导的中药-化学药物相互作用研究
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摘要
中药及其制剂作为临床上重要治疗手段常与化学药物联合使用,因此,应关注中药与化学药物之间的相互作用。乳腺癌耐药蛋白(Breast Cancer Resistance Protein,BCRP)是重要的外排转运体之一,参与体内诸多药物的吸收、分布、代谢、排泄过程。BCRP的表达和外排活性常受相关底物或抑制剂影响,进而改变联合用药的药代动力学,导致药物相互作用。本文主要就银杏、姜黄、甘草、人参、黄芪等常见中药及其主要成分对BCRP的影响及其可能引起的药物相互作用进行综述,为规避临床中药-化学药物联合用药风险提供科学依据。
Traditional Chinese medicine(TCM) and its preparations are often used together with chemical drugs as an important therapeutic means in clinical practice. Therefore, attention should be paid to the interaction between traditional Chinese medicines and chemical drugs. BCRP(Breast Cancer Resistance Protein) is one of the most important efflux transporters involved in the absorption, distribution, metabolism and excretion of many drugs in the body. The expression and efflux activity of BCRP are often affected by related substrates or inhibitors, resulting in the pharmacokinetic change of the combined drugs and herb-drug interactions. This paper will mainly review the effects of the commonly used traditional Chinese medicines such as ginkgo, turmeric, liquorice root, ginseng and astragali radix on BCRP and the possible herb-drug interactions, so as to provide scientific basis for avoiding the risk of clinical herb-drug combination.
Traditional Chinese medicine(TCM) and its preparations are often used together with chemical drugs as an important therapeutic means in clinical practice. Therefore, attention should be paid to the interaction between traditional Chinese medicines and chemical drugs. BCRP(Breast Cancer Resistance Protein) is one of the most important efflux transporters involved in the absorption, distribution, metabolism and excretion of many drugs in the body. The expression and efflux activity of BCRP are often affected by related substrates or inhibitors, resulting in the pharmacokinetic change of the combined drugs and herb-drug interactions. This paper will mainly review the effects of the commonly used traditional Chinese medicines such as ginkgo, turmeric, liquorice root, ginseng and astragali radix on BCRP and the possible herb-drug interactions, so as to provide scientific basis for avoiding the risk of clinical herb-drug combination.
引文
1 Kruijtzer C M, Beijnen JH, Rosing H, et al. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and p-glycoprotein Inhibitor GF120918. J Clin Oncol, 2002, 20(13):2943-2950.
2 Bae S H, Park WS, Han S, et al. Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.Korean J Physiol Pharmacol.2018, 22(3):321-329
3 Nakanishi T, Doyle LA, Hassel B, et al. Functional characterization of human breast cancer resistance protein(BCRP, ABCG2)expressed in the oocytes of xenopus laevis. Mol Pharmacol, 2003, 64:1452-1462.
4 Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res, 2001, 61(8):3458-3464.
5 Cooray HC, Blackmore CG, Maskell L, et al. Localisation of breast cancer resistance protein in microvessel endothelium of human brain.Neuroreport, 2002, 13(16):2059-2063.
6 Natarajan K, Xie Y, Baer M R, et al. Role of breast cancer resistance protein(BCRP/ABCG2)in cancer drug resistance. Biochem Pharmacol,2012, 83(8):1084-1103.
7 Stacy A E, Jansson P J, Richardson D R. Molecular pharmacology of ABCG2and its role in chemoresistance. Mol Pharmacol, 2013, 84:655-669.
8 Imai Y, Tsukahara S, Asada S, et al. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance.Cancer Res, 2004, 64(12):4346-4352.
9 Schinkel A H, Valk MAVD, Allen N D, et al. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.Mol Cancer Ther, 2002, 1(6):417-425.
10 Van LA, Allen J D, Schinkel A H, et al. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg Med Chem Lett, 2001, 11(1):29-32.
11 Mao Q, Unadkat J D. Role of the breast cancer resistance protein(BCRP/ABCG2)in drug transport-an update. AAPS J, 2015, 17(1):65-82.
12 Kühnle M, Egger M, Müller C, et al. Potent and selective inhibitors of breast cancer resistance protein(ABCG2)derived from the p-glycoprotein(ABCB1)modulator tariquidar. J Med Chem, 2009, 52(4):1190-1197.
13 Bircsak M, Kristin L A. Interaction of Isoflavones with the BCRP/ABCG2 Drug Transporter. Curr Drug Metab,2015,16(2):124-140.
14 An G, Gallegos J, Morris ME. The bioflavonoid kaempferol is an Abcg2substrate and inhibits Abcg2-mediated quercetin efflux. Drug Metab Dispos, 2011, 39(3):426-432.
15 Moon Y J, Morris M E. Pharmacokinetics and bioavailability of the bioflavonoid biochanin A:effects of quercetin and EGCG on biochanin A disposition in rats. Mol Pharm, 2007, 4(6):865-872.
16 Kristin M, Vivek G, Poi YSY, et al. Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter.J Pharmacol Exp Ther, 2016, 357:103-113
17 Kunnumakkara A B, Bordoloi D, Padmavathi G, et al. Curcumin, The Golden Nutraceutical:Multitargeting for Multiple Chronic Diseases. Br J Pharmacol, 2017, 174(11):1325-1348.
18 Karibe T, Imaoka T, Abe K, et al. Curcumin as an in vivo selective intestinal breast cancer resistance protein inhibitor in cynomolgus monkeys. Drug Metab Dispos, 2018, 46(5):667-679.
19 Liu H, Rao D K, Ambudkar S V, et al. A combination of curcumin with either gramicidin or ouabain selectively kills cells that express the multidrug resistance-linked ABCG2 transporter. Biophys J, 2015, 108(2):145.
20 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. Toxicol Sci, 2007, 96(2):227-236.
21 Shukla M, Malik M Y, Jaiswal S, et al. A mechanistic investigation of the bioavailability enhancing potential of lysergol,a novel bioenhancer,using curcumin. RSC Adv, 2016, 6(64):58933-58942.
22 Feng X, Ding L, Qiu F. Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid. Drug Metab Rev, 2015, 47(2):229-238.
23 Peng Y, Fan M, Peng C, et al. Alleviating the intestinal absorption of rhein in rhubarb through herb compatibility in tiaowei chengqi tang in Caco-2Cells. Evid Based Complement Alternat Med, 2018, 2018(3):593.
24 Matsuo K, Takenaka K, Shimomura H, et al. Lamivudine and glycyrrhizin for treatment of chemotherapy-induced hepatitis B virus(HBV)hepatitis in a chronic HBV carrier with non-Hodgkin lymphoma. Leuk Lymphoma,2001, 41(1-2):191-195.
25 Chen Q, Chen H, Wang W, et al. Glycyrrhetic acid, but not glycyrrhizic acid, strengthened entecavir activity by promoting its subcellular distribution in the liver via efflux inhibition. Eur J Pharm Sci, 2017,106:313-327.
26 宋齐.人参化学成分和药理作用研究进展.人参研究, 2017, 29(2):47-54.
27 Jin J, Shahi S, Kang H K, et al. Metabolites of ginsenosides as novel BCRP inhibitors. Biochem Biophys Res Commun, 2006, 345(4):1308-1314.
28 Jiang R, Dong J, Li X, et al. Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenosideperpetrated herb-drug interactions on OATP1B3. Br J Pharmacol, 2015,172(4):1059-1073.
29 孙政华,邵晶,郭玫.黄芪化学成分及药理作用研究进展.中医临床研究, 2015(25):22-25.
30 Zhang G, Ou R, Li F, et al. Regulation of drug-metabolizing enzymes and efflux transporters by Astragali radix decoction and its main bioactive compounds:Implication for clinical drug-drug interactions. J Ethnopharmacol,2016, 180:104-113.
31 Lou Y, Guo Z, Zhu Y, et al. Astragali radix and its main bioactive compounds activate the Nrf2-mediated signaling pathway to induce Pglycoprotein and breast cancer resistance protein. J Ethnopharmacol,2018, 228:82-91.
32 Zhao Q, Chen X Y, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull, 2016, 61(18):1391-1398.
33 Yu C P, Hsieh Y C, Shia C S, et al. Increased systemic exposure of methotrexate by a polyphenol-rich herb via modulation on efflux transporters multidrug resistance-associated protein 2 and breast cancer resistance protein.J Pharm Sci, 2016, 105(1):343-349.
34 Peng Y, Wang S, Wang M, et al. Dual effects on constipation and diarrhea:Protective potential of Radix Inulae lactones on irritable bowel syndrome. Rsc Advances, 2016, 6(97):94486-94495.
35 Zhu M L, Liang X L, Zhao L J, et al. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model.J Ethnopharmacol, 2013, 150(2):553-559.
36 Xu M L, Liang X L, Zhao L J, et al. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model. J Ethnopharmacol, 2013, 150(2):553-559.
37 Jeong-Hyeon K, Gautam S, Jae-Young U,et al. The Role of Resveratrol in Cancer Therapy. Int J M Sci, 2017, 18(12):2589-.
38 Wetering K V D, 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. Mol Pharm, 2009, 75(4):876-885.
39 Juan M E, González-Pons E, Planas J M. Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. J Nutr,2010, 140(3):489-495.
40 Alfaras I, Pérez M, Juan M E, et al. Involvement of breast cancer resistance protein(BCRP1/ABCG2)in the bioavailability and tissue distribution of trans-resveratrol in knockout mice. J Agric Food Chem,2010, 58(7):4523-4528.
41 El-Sheikh A A, Morsy M A, Al-Taher A Y. Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2. Fundam Clin Pharmacol, 2016, 30(5):406-418.
42 Fleisher B, Unum J, Shao J, et al. Ingredients in fruit juices interact with dasatinib through inhibition of BCRP:a new mechanism of beveragedrug interaction. J Pharm Sci, 2015, 104(1):266-275.
43 Wen J H, Xiong Y Q. The effect of herbal medicine danshensu and ursolic acid on pharmacokinetics of rosuvastatin in rats. Eur J Drug Metab Pharmacokinet, 2011, 36(4):205-211.
44 Yin Y, Yang M, Wang Y, et al. Tanshinone IIA Increases mRNA expression of efflux transporters in cultured human intestinal cell. Am J Chin Med, 2010, 38(05):995-1004.
45 Jia W, Du F, Liu X, et al. Renal tubular secretion of tanshinol:molecular mechanism, impact on its systemic exposure and propensity for dose-related nephrotoxicity and renal herb-drug interactions. Drug Metab Dispos, 2015, 43(5):669-678.
46 Wada K, Nihira M, Hayakawa H, et al. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice. Forensic Sci Int, 2005, 148(1):21-29.
47 Wu J J, Zhu Y F, Guo Z Z, et al. Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway. Phytomedicine, 2018,44:87-97.
48 Wu J J, Guo Z Z, Zhu Y F, et al. A systematic review of pharmacokinetic studies on herbal drug Fuzi:Implications for Fuzi as personalized medicine. Phytomedicine, 2018, 44:187-203.
49 Tan K W, Yan L, Paxton J W, et al. Identification of novel dietary phytochemicals inhibiting the efflux transporter breast cancer resistance protein(BCRP/ABCG2). Food Chem, 2013, 138(4):2267-2274.
2 Bae S H, Park WS, Han S, et al. Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.Korean J Physiol Pharmacol.2018, 22(3):321-329
3 Nakanishi T, Doyle LA, Hassel B, et al. Functional characterization of human breast cancer resistance protein(BCRP, ABCG2)expressed in the oocytes of xenopus laevis. Mol Pharmacol, 2003, 64:1452-1462.
4 Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res, 2001, 61(8):3458-3464.
5 Cooray HC, Blackmore CG, Maskell L, et al. Localisation of breast cancer resistance protein in microvessel endothelium of human brain.Neuroreport, 2002, 13(16):2059-2063.
6 Natarajan K, Xie Y, Baer M R, et al. Role of breast cancer resistance protein(BCRP/ABCG2)in cancer drug resistance. Biochem Pharmacol,2012, 83(8):1084-1103.
7 Stacy A E, Jansson P J, Richardson D R. Molecular pharmacology of ABCG2and its role in chemoresistance. Mol Pharmacol, 2013, 84:655-669.
8 Imai Y, Tsukahara S, Asada S, et al. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance.Cancer Res, 2004, 64(12):4346-4352.
9 Schinkel A H, Valk MAVD, Allen N D, et al. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.Mol Cancer Ther, 2002, 1(6):417-425.
10 Van LA, Allen J D, Schinkel A H, et al. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg Med Chem Lett, 2001, 11(1):29-32.
11 Mao Q, Unadkat J D. Role of the breast cancer resistance protein(BCRP/ABCG2)in drug transport-an update. AAPS J, 2015, 17(1):65-82.
12 Kühnle M, Egger M, Müller C, et al. Potent and selective inhibitors of breast cancer resistance protein(ABCG2)derived from the p-glycoprotein(ABCB1)modulator tariquidar. J Med Chem, 2009, 52(4):1190-1197.
13 Bircsak M, Kristin L A. Interaction of Isoflavones with the BCRP/ABCG2 Drug Transporter. Curr Drug Metab,2015,16(2):124-140.
14 An G, Gallegos J, Morris ME. The bioflavonoid kaempferol is an Abcg2substrate and inhibits Abcg2-mediated quercetin efflux. Drug Metab Dispos, 2011, 39(3):426-432.
15 Moon Y J, Morris M E. Pharmacokinetics and bioavailability of the bioflavonoid biochanin A:effects of quercetin and EGCG on biochanin A disposition in rats. Mol Pharm, 2007, 4(6):865-872.
16 Kristin M, Vivek G, Poi YSY, et al. Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter.J Pharmacol Exp Ther, 2016, 357:103-113
17 Kunnumakkara A B, Bordoloi D, Padmavathi G, et al. Curcumin, The Golden Nutraceutical:Multitargeting for Multiple Chronic Diseases. Br J Pharmacol, 2017, 174(11):1325-1348.
18 Karibe T, Imaoka T, Abe K, et al. Curcumin as an in vivo selective intestinal breast cancer resistance protein inhibitor in cynomolgus monkeys. Drug Metab Dispos, 2018, 46(5):667-679.
19 Liu H, Rao D K, Ambudkar S V, et al. A combination of curcumin with either gramicidin or ouabain selectively kills cells that express the multidrug resistance-linked ABCG2 transporter. Biophys J, 2015, 108(2):145.
20 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. Toxicol Sci, 2007, 96(2):227-236.
21 Shukla M, Malik M Y, Jaiswal S, et al. A mechanistic investigation of the bioavailability enhancing potential of lysergol,a novel bioenhancer,using curcumin. RSC Adv, 2016, 6(64):58933-58942.
22 Feng X, Ding L, Qiu F. Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid. Drug Metab Rev, 2015, 47(2):229-238.
23 Peng Y, Fan M, Peng C, et al. Alleviating the intestinal absorption of rhein in rhubarb through herb compatibility in tiaowei chengqi tang in Caco-2Cells. Evid Based Complement Alternat Med, 2018, 2018(3):593.
24 Matsuo K, Takenaka K, Shimomura H, et al. Lamivudine and glycyrrhizin for treatment of chemotherapy-induced hepatitis B virus(HBV)hepatitis in a chronic HBV carrier with non-Hodgkin lymphoma. Leuk Lymphoma,2001, 41(1-2):191-195.
25 Chen Q, Chen H, Wang W, et al. Glycyrrhetic acid, but not glycyrrhizic acid, strengthened entecavir activity by promoting its subcellular distribution in the liver via efflux inhibition. Eur J Pharm Sci, 2017,106:313-327.
26 宋齐.人参化学成分和药理作用研究进展.人参研究, 2017, 29(2):47-54.
27 Jin J, Shahi S, Kang H K, et al. Metabolites of ginsenosides as novel BCRP inhibitors. Biochem Biophys Res Commun, 2006, 345(4):1308-1314.
28 Jiang R, Dong J, Li X, et al. Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenosideperpetrated herb-drug interactions on OATP1B3. Br J Pharmacol, 2015,172(4):1059-1073.
29 孙政华,邵晶,郭玫.黄芪化学成分及药理作用研究进展.中医临床研究, 2015(25):22-25.
30 Zhang G, Ou R, Li F, et al. Regulation of drug-metabolizing enzymes and efflux transporters by Astragali radix decoction and its main bioactive compounds:Implication for clinical drug-drug interactions. J Ethnopharmacol,2016, 180:104-113.
31 Lou Y, Guo Z, Zhu Y, et al. Astragali radix and its main bioactive compounds activate the Nrf2-mediated signaling pathway to induce Pglycoprotein and breast cancer resistance protein. J Ethnopharmacol,2018, 228:82-91.
32 Zhao Q, Chen X Y, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull, 2016, 61(18):1391-1398.
33 Yu C P, Hsieh Y C, Shia C S, et al. Increased systemic exposure of methotrexate by a polyphenol-rich herb via modulation on efflux transporters multidrug resistance-associated protein 2 and breast cancer resistance protein.J Pharm Sci, 2016, 105(1):343-349.
34 Peng Y, Wang S, Wang M, et al. Dual effects on constipation and diarrhea:Protective potential of Radix Inulae lactones on irritable bowel syndrome. Rsc Advances, 2016, 6(97):94486-94495.
35 Zhu M L, Liang X L, Zhao L J, et al. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model.J Ethnopharmacol, 2013, 150(2):553-559.
36 Xu M L, Liang X L, Zhao L J, et al. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model. J Ethnopharmacol, 2013, 150(2):553-559.
37 Jeong-Hyeon K, Gautam S, Jae-Young U,et al. The Role of Resveratrol in Cancer Therapy. Int J M Sci, 2017, 18(12):2589-.
38 Wetering K V D, 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. Mol Pharm, 2009, 75(4):876-885.
39 Juan M E, González-Pons E, Planas J M. Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. J Nutr,2010, 140(3):489-495.
40 Alfaras I, Pérez M, Juan M E, et al. Involvement of breast cancer resistance protein(BCRP1/ABCG2)in the bioavailability and tissue distribution of trans-resveratrol in knockout mice. J Agric Food Chem,2010, 58(7):4523-4528.
41 El-Sheikh A A, Morsy M A, Al-Taher A Y. Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2. Fundam Clin Pharmacol, 2016, 30(5):406-418.
42 Fleisher B, Unum J, Shao J, et al. Ingredients in fruit juices interact with dasatinib through inhibition of BCRP:a new mechanism of beveragedrug interaction. J Pharm Sci, 2015, 104(1):266-275.
43 Wen J H, Xiong Y Q. The effect of herbal medicine danshensu and ursolic acid on pharmacokinetics of rosuvastatin in rats. Eur J Drug Metab Pharmacokinet, 2011, 36(4):205-211.
44 Yin Y, Yang M, Wang Y, et al. Tanshinone IIA Increases mRNA expression of efflux transporters in cultured human intestinal cell. Am J Chin Med, 2010, 38(05):995-1004.
45 Jia W, Du F, Liu X, et al. Renal tubular secretion of tanshinol:molecular mechanism, impact on its systemic exposure and propensity for dose-related nephrotoxicity and renal herb-drug interactions. Drug Metab Dispos, 2015, 43(5):669-678.
46 Wada K, Nihira M, Hayakawa H, et al. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice. Forensic Sci Int, 2005, 148(1):21-29.
47 Wu J J, Zhu Y F, Guo Z Z, et al. Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway. Phytomedicine, 2018,44:87-97.
48 Wu J J, Guo Z Z, Zhu Y F, et al. A systematic review of pharmacokinetic studies on herbal drug Fuzi:Implications for Fuzi as personalized medicine. Phytomedicine, 2018, 44:187-203.
49 Tan K W, Yan L, Paxton J W, et al. Identification of novel dietary phytochemicals inhibiting the efflux transporter breast cancer resistance protein(BCRP/ABCG2). Food Chem, 2013, 138(4):2267-2274.
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