表没食子儿茶素表没食子酸酯对药物代谢酶和转运体影响的研究进展
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摘要
作为茶叶中含量最高的儿茶素类物质,表没食子儿茶素表没食子酸酯[(-)-epigallocatechin-3-gallate,EGCG]具有多种生物活性。越来越多的研究表明,EGCG对药物代谢酶和转运体均有调控作用,药物代谢酶主要包括Ⅰ相代谢酶细胞色素P450家族(cytochromes P450,CYP)和Ⅱ相代谢酶尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyltransferase,UGT)、硫酸基转移酶(sulfotransferase,SULT),转运体主要包括有机阴离子转运多肽(organic anion transporter polypeptides,OATPs),有机阳离子转运体家族(organic cation transporters,OCTs)和外排转运体P-糖蛋白(P-glycoprotein,P-gp)。EGCG的调控作用使得其在与许多药物(如他莫昔芬、地尔硫艹卓和辛伐他汀)合用时,药物在体内的药动学发生改变。通过查阅了近年来国内外相关研究,就EGCG对药物代谢酶和转运体的调控及药物相互作用进行了综述。
As the most abundant catechin in tea,(-)-epigallocatechin-3-gallate( EGCG) has a variety of biological activities. More and more studies have shown that EGCG could regulate drug-metabolizing enzymes and transporters. The drug metabolizing enzymes mainly include the phase Ⅰ metabolizing enzymes cytochromes P450( CYP) and the phase Ⅱ metabolic enzymes UDP-glucuronosyltransferase( UGT) and sulfotransferase( SULT),and the drug transporters mainly include organic anion transporter polypeptides( OATPs),organic cation transporters( OCTs) and efflux transporter P-glycoprotein( P-gp). The regulation of EGCG has led to the changes in the pharmacokinetics of many drugs,such as tamoxifen,diltiazem and simvastatin.In the paper,the regulation of drug metabolism enzymes and transporters,as well as the pharmacokinetics by EGCG were summarized by reviewing the related researches from home and abroad in recent years.
As the most abundant catechin in tea,(-)-epigallocatechin-3-gallate( EGCG) has a variety of biological activities. More and more studies have shown that EGCG could regulate drug-metabolizing enzymes and transporters. The drug metabolizing enzymes mainly include the phase Ⅰ metabolizing enzymes cytochromes P450( CYP) and the phase Ⅱ metabolic enzymes UDP-glucuronosyltransferase( UGT) and sulfotransferase( SULT),and the drug transporters mainly include organic anion transporter polypeptides( OATPs),organic cation transporters( OCTs) and efflux transporter P-glycoprotein( P-gp). The regulation of EGCG has led to the changes in the pharmacokinetics of many drugs,such as tamoxifen,diltiazem and simvastatin.In the paper,the regulation of drug metabolism enzymes and transporters,as well as the pharmacokinetics by EGCG were summarized by reviewing the related researches from home and abroad in recent years.
引文
1刘洋.儿茶素在小鼠体内代谢动力学及其对代谢酶CYP3A4和芳香化酶作用研究[D].杭州:中国计量学院硕士学位论文,2014
2毛小强,那万里,赵丹,等.茶多酚对前列腺癌PC-3M细胞增殖与凋亡的影响[J].中国实验诊断学,2010,14(2):170-173
3傅颖,梅松,陈建国,等.茶多酚对高脂大鼠体重及血清中脂代谢水平的影响[J].中国卫生检验杂志,2009,19(11):2506-2508
4陈悦,刘秋慧.茶多酚对豚鼠心肌细胞钙电流及动作电位的影响[J].中国药学杂志,2010,45(3):190-192
5葛建,林芳,李明揆,等.表没食子儿茶素没食子酸酯(EGCG)生物活性研究进展[J].安徽农业大学学报,2011,38(2):156-163
6 Bohmdorfer M,Maier-Salamon A,Riha J,et al.Interplay of drug metabolizing enzymes with cellular transporters[J].Wien Med Wochenschr,2014,164(21-22):461-471
7范景辉,张毕奎.姜黄素对药物代谢酶和转运体影响的研究进展[J].中南药学,2011,9(7):528-532
8侯健,孙娥,宋捷,等.肝脏药物代谢酶CYP450与中药肝毒性的关系[J].中国中药杂志,2016,41(15):2774-2780
9 Zhou S,Chan E,Duan W,et al.Drug bioactivation,covalent binding to target proteins and toxicity relevance[J].Drug Metab Rev,2005,37(1):41-213
10刘晓强,袁淋文,臧敏,等.评价HPPH对细胞色素P450酶体外代谢活性的影响[J].药学与临床研究,2014,22(1):29-33
11 Zanger UM,Schwab M.Cytochrome P450 enzymes in drug metabolism:regulation of gene expression,enzyme activities,and impact of genetic variation[J].Pharmacol Ther,2013,138(1):103-141
12 Satoh T,Fujisawa H,Nakamura A,et al.Inhibitory effects of eight green tea catechins on cytochrome P450 1A2,2C9,2D6,and3A4 activities[J].J Pharm Pharm Sci,2016,19(2):188-197
13 Misaka S,Kawabe K,Onoue S,et al.Effects of green tea catechins on cytochrome P450 2B6,2C8,2C19,2D6 and 3Aactivities in human liver and intestinal microsomes[J].Drug Metab Pharmacokinet,2013,28(3):244-249
14 Muto S,Fujita K,Yamazaki Y,et al.Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450[J].Mutat Res,2001,479(1-2):197-206
15杨婷玉,刘亚妮,师少军.槲皮素对药物代谢酶调控作用的研究进展[J].中国药师,2016,19(3):555-559
16高欣,吴疆,袁永兵,等.尿苷二磷酸葡萄糖醛酸转移酶与内源性物质的相互作用[J].药物评价研究,2015,38(4):421-428
17张艳,郝海平,王广基.尿苷二磷酸葡萄糖醛酸转移酶介导的药物相互作用的研究进展[J].中国临床药理学与治疗学,2011,16(4):447-454
18 Guillemette C,Levesque E,Harvey M,et al.UGT genomic diversity:beyond gene duplication[J].Drug Metab Rev,2010,42(1):24-44
19 Mohamed MF,Tseng T,Frye RF.Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity[J].Xenobiotica,2010,40(10):663-669
20 Lu H,Meng X,Li C,et al.Glucuronides of tea catechins:enzymology of biosynthesis and biological activities[J].Drug Metab Dispos,2003,31(4):452-461
21 Cook I,Wang T,Falany CN,et al.The allosteric binding sites of sulfotransferase 1A1[J].Drug Metab Dispos,2015,43(3):418-423
22 Coughtrie MW,Johnston LE.Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance[J].Drug Metab Dispos,2001,29(4 Pt 2):522-528
23 Cook I,Wang T,Girvin M,et al.The structure of the catechin-binding site of human sulfotransferase 1A1[J].Proc Natl Acad Sci USA,2016,113(50):14312-14317
24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
25 Giacomini KM,Huang SM,Tweedie DJ,et al.Membrane transporters in drug development[J].Nat Rev Drug Discov,2010,9(3):215-236
26肖熠,黄鑫,江振洲,等.有机阴离子转运多肽介导的药物相互作用研究进展[J].药学与临床研究,2014,22(3):257-261
27 Shitara Y,Maeda K,Ikejiri K,et al.Clinical significance of organic anion transporting polypeptides(OATPs)in drug disposition:their roles in hepatic clearance and intestinal absorption[J].Biopharm Drug Dispos,2013,34(1):45-78
28 Wang X,Wolkoff AW,Morris ME.Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1(OATP-C)modulators[J].Drug Metab Dispos,2005,33(11):1666-1672
29 Fuchikami H,Satoh H,Tsujimoto M,et al.Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B[J].Drug Metab Dispos,2006,34(4):577-582
30 Roth M,Timmermann BN,Hagenbuch B.Interactions of green tea catechins with organic anion-transporting polypeptides[J].Drug Metab Dispos,2011,39(5):920-926
31 Leslie EM,Deeley RG,Cole SP.Multidrug resistance proteins:role of P-glycoprotein,MRP1,MRP2,and BCRP(ABCG2)in tissue defense[J].Toxicol Appl Pharmacol,2005,204(3):216-237
32梁晓玲,冯立影,孙德春,等.中药对P-糖蛋白的影响及机制的研究进展[J].实用药物与临床,2016,19(1):96-104
33 Jodoin J,Demeule M,Beliveau R.Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols[J].Biochim Biophys Acta,2002,1542(1-3):149-159
34 Hong J,Lambert JD,Lee SH,et al.Involvement of multidrug resistance-associated proteins in regulating cellular levels of(-)-epigallocatechin-3-gallate and its methyl metabolites[J].Biochem Biophys Res Commun,2003,310(1):222-227
35 Kitagawa S,Nabekura T,Kamiyama S.Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells[J].JPharm Pharmacol,2004,56(8):1001-1005
36熊宗萍,朱鹏,黄师琼,等.多药及毒素外排转运蛋白遗传药理学研究进展[J].中国药理学通报,2016,32(12):1639-1643
37 Knop J,Misaka S,Singer K,et al.Inhibitory effects of green tea and(-)-epigallocatechin gallate on transport by OATP1B1,OATP1B3,OCT1,OCT2,MATE1,MATE2-K and P-Glycoprotein[J].Plos One,2015,10(10):e139370
38 Chow HH,Hakim IA,Vining DR,et al.Effects of repeated green tea catechin administration on human cytochrome P450activity[J].Cancer Epidemiol Biomarkers Prev,2006,15(12):2473-2476
39 Donovan JL,Chavin KD,Devane CL,et al.Green tea(Camellia sinensis)extract does not alter cytochrome p450 3A4 or 2D6activity in healthy volunteers[J].Drug Metab Dispos,2004,32(9):906-908
40 Shin SC,Choi JS.Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite,4-hydroxytamoxifen,in rats[J].Anticancer Drugs,2009,20(7):584-588
41 Li C,Choi JS.Effects of epigallocatechin gallate on the bioavailability and pharmacokinetics of diltiazem in rats[J].Pharmazie,2008,63(11):815-818
42 Chung JH,Choi DH,Choi JS.Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats[J].Biopharm Drug Dispos,2009,30(2):90-93
43 Yang W,Zhang Q,Yang Y,et al.Epigallocatechin-3-gallate decreases the transport and metabolism of simvastatin in rats[J].Xenobiotica,2017,47(1):86-92
44 Kim TE,Ha N,Kim Y,et al.Effect of epigallocatechin-3-gallate,major ingredient of green tea,on the pharmacokinetics of rosuvastatin in healthy volunteers[J].Drug Des Devel Ther,2017,11:1409-1416
2毛小强,那万里,赵丹,等.茶多酚对前列腺癌PC-3M细胞增殖与凋亡的影响[J].中国实验诊断学,2010,14(2):170-173
3傅颖,梅松,陈建国,等.茶多酚对高脂大鼠体重及血清中脂代谢水平的影响[J].中国卫生检验杂志,2009,19(11):2506-2508
4陈悦,刘秋慧.茶多酚对豚鼠心肌细胞钙电流及动作电位的影响[J].中国药学杂志,2010,45(3):190-192
5葛建,林芳,李明揆,等.表没食子儿茶素没食子酸酯(EGCG)生物活性研究进展[J].安徽农业大学学报,2011,38(2):156-163
6 Bohmdorfer M,Maier-Salamon A,Riha J,et al.Interplay of drug metabolizing enzymes with cellular transporters[J].Wien Med Wochenschr,2014,164(21-22):461-471
7范景辉,张毕奎.姜黄素对药物代谢酶和转运体影响的研究进展[J].中南药学,2011,9(7):528-532
8侯健,孙娥,宋捷,等.肝脏药物代谢酶CYP450与中药肝毒性的关系[J].中国中药杂志,2016,41(15):2774-2780
9 Zhou S,Chan E,Duan W,et al.Drug bioactivation,covalent binding to target proteins and toxicity relevance[J].Drug Metab Rev,2005,37(1):41-213
10刘晓强,袁淋文,臧敏,等.评价HPPH对细胞色素P450酶体外代谢活性的影响[J].药学与临床研究,2014,22(1):29-33
11 Zanger UM,Schwab M.Cytochrome P450 enzymes in drug metabolism:regulation of gene expression,enzyme activities,and impact of genetic variation[J].Pharmacol Ther,2013,138(1):103-141
12 Satoh T,Fujisawa H,Nakamura A,et al.Inhibitory effects of eight green tea catechins on cytochrome P450 1A2,2C9,2D6,and3A4 activities[J].J Pharm Pharm Sci,2016,19(2):188-197
13 Misaka S,Kawabe K,Onoue S,et al.Effects of green tea catechins on cytochrome P450 2B6,2C8,2C19,2D6 and 3Aactivities in human liver and intestinal microsomes[J].Drug Metab Pharmacokinet,2013,28(3):244-249
14 Muto S,Fujita K,Yamazaki Y,et al.Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450[J].Mutat Res,2001,479(1-2):197-206
15杨婷玉,刘亚妮,师少军.槲皮素对药物代谢酶调控作用的研究进展[J].中国药师,2016,19(3):555-559
16高欣,吴疆,袁永兵,等.尿苷二磷酸葡萄糖醛酸转移酶与内源性物质的相互作用[J].药物评价研究,2015,38(4):421-428
17张艳,郝海平,王广基.尿苷二磷酸葡萄糖醛酸转移酶介导的药物相互作用的研究进展[J].中国临床药理学与治疗学,2011,16(4):447-454
18 Guillemette C,Levesque E,Harvey M,et al.UGT genomic diversity:beyond gene duplication[J].Drug Metab Rev,2010,42(1):24-44
19 Mohamed MF,Tseng T,Frye RF.Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity[J].Xenobiotica,2010,40(10):663-669
20 Lu H,Meng X,Li C,et al.Glucuronides of tea catechins:enzymology of biosynthesis and biological activities[J].Drug Metab Dispos,2003,31(4):452-461
21 Cook I,Wang T,Falany CN,et al.The allosteric binding sites of sulfotransferase 1A1[J].Drug Metab Dispos,2015,43(3):418-423
22 Coughtrie MW,Johnston LE.Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance[J].Drug Metab Dispos,2001,29(4 Pt 2):522-528
23 Cook I,Wang T,Girvin M,et al.The structure of the catechin-binding site of human sulfotransferase 1A1[J].Proc Natl Acad Sci USA,2016,113(50):14312-14317
24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
25 Giacomini KM,Huang SM,Tweedie DJ,et al.Membrane transporters in drug development[J].Nat Rev Drug Discov,2010,9(3):215-236
26肖熠,黄鑫,江振洲,等.有机阴离子转运多肽介导的药物相互作用研究进展[J].药学与临床研究,2014,22(3):257-261
27 Shitara Y,Maeda K,Ikejiri K,et al.Clinical significance of organic anion transporting polypeptides(OATPs)in drug disposition:their roles in hepatic clearance and intestinal absorption[J].Biopharm Drug Dispos,2013,34(1):45-78
28 Wang X,Wolkoff AW,Morris ME.Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1(OATP-C)modulators[J].Drug Metab Dispos,2005,33(11):1666-1672
29 Fuchikami H,Satoh H,Tsujimoto M,et al.Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B[J].Drug Metab Dispos,2006,34(4):577-582
30 Roth M,Timmermann BN,Hagenbuch B.Interactions of green tea catechins with organic anion-transporting polypeptides[J].Drug Metab Dispos,2011,39(5):920-926
31 Leslie EM,Deeley RG,Cole SP.Multidrug resistance proteins:role of P-glycoprotein,MRP1,MRP2,and BCRP(ABCG2)in tissue defense[J].Toxicol Appl Pharmacol,2005,204(3):216-237
32梁晓玲,冯立影,孙德春,等.中药对P-糖蛋白的影响及机制的研究进展[J].实用药物与临床,2016,19(1):96-104
33 Jodoin J,Demeule M,Beliveau R.Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols[J].Biochim Biophys Acta,2002,1542(1-3):149-159
34 Hong J,Lambert JD,Lee SH,et al.Involvement of multidrug resistance-associated proteins in regulating cellular levels of(-)-epigallocatechin-3-gallate and its methyl metabolites[J].Biochem Biophys Res Commun,2003,310(1):222-227
35 Kitagawa S,Nabekura T,Kamiyama S.Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells[J].JPharm Pharmacol,2004,56(8):1001-1005
36熊宗萍,朱鹏,黄师琼,等.多药及毒素外排转运蛋白遗传药理学研究进展[J].中国药理学通报,2016,32(12):1639-1643
37 Knop J,Misaka S,Singer K,et al.Inhibitory effects of green tea and(-)-epigallocatechin gallate on transport by OATP1B1,OATP1B3,OCT1,OCT2,MATE1,MATE2-K and P-Glycoprotein[J].Plos One,2015,10(10):e139370
38 Chow HH,Hakim IA,Vining DR,et al.Effects of repeated green tea catechin administration on human cytochrome P450activity[J].Cancer Epidemiol Biomarkers Prev,2006,15(12):2473-2476
39 Donovan JL,Chavin KD,Devane CL,et al.Green tea(Camellia sinensis)extract does not alter cytochrome p450 3A4 or 2D6activity in healthy volunteers[J].Drug Metab Dispos,2004,32(9):906-908
40 Shin SC,Choi JS.Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite,4-hydroxytamoxifen,in rats[J].Anticancer Drugs,2009,20(7):584-588
41 Li C,Choi JS.Effects of epigallocatechin gallate on the bioavailability and pharmacokinetics of diltiazem in rats[J].Pharmazie,2008,63(11):815-818
42 Chung JH,Choi DH,Choi JS.Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats[J].Biopharm Drug Dispos,2009,30(2):90-93
43 Yang W,Zhang Q,Yang Y,et al.Epigallocatechin-3-gallate decreases the transport and metabolism of simvastatin in rats[J].Xenobiotica,2017,47(1):86-92
44 Kim TE,Ha N,Kim Y,et al.Effect of epigallocatechin-3-gallate,major ingredient of green tea,on the pharmacokinetics of rosuvastatin in healthy volunteers[J].Drug Des Devel Ther,2017,11:1409-1416