<i>CYP2C19</i>基因多态性与个体化治疗的研究进展_West China Medical Journal

Authors：

 刘雯 ,  苗佳

四川大学华西医院Ⅰ期临床研究室（成都，610041）;

Corresponding author：

苗佳, Email: miaosiyi1971@163.com

Keywords：

CYP2C19; 基因多态性; 个体化治疗

DOI：

10.7507/1002-0179.20140721

Video：

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CYP2C19作为细胞色素P450重要的酶系之一，参与了多种药物的体内代谢过程。CYP2C19编码基因的突变，可造成CYP2C19酶代谢活性的改变，进而出现不同患者服用以CYP2C19为关键代谢酶的药物后，体内血药浓度差异，甚至产生不同临床反应。通过对CYP2C19基因多态性及与之相关的个体化治疗研究进展的综述，旨在为临床合理用药提供参考资料。

Citation： 刘雯, 苗佳. CYP2C19基因多态性与个体化治疗的研究进展. West China Medical Journal, 2014, 29(12): 2382-2386. doi: 10.7507/1002-0179.20140721 Copy

1.	Wroblewski B, Glenn MB. The cytochrome p-450 drug metabolizing enzyme system:an overview of potential clinically important drug interactions[J]. J Head Trauma Rehabil, 2002, 17(6):571-574.
2.	Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P4502C19:correlation between 2C19 and S-mephenytoin 4'-hydroxylation[J]. Arch Biochem Biophys, 1993, 306(1):240-245.
3.	He N, Yan FX, Huang SL, et al. CYP2C19 genotype and S-mephenytoin 4'-hydroxylation phenotype in a Chinese Dai population[J]. Eur J Clin Pharmacol, 2002, 58(1):15-18.
4.	Finta C, Zaphiropoulos PG. The human CYP2C locus:a prototype for intergenic and exon repetition splicing events[J]. Genomics, 2000, 63(3):433-438.
5.	De Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans[J]. J Biol Chem, 1994, 269(22):15419-15422.
6.	De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese[J]. Mol Pharmacol, 1994, 46(4):594-598.
7.	Shimizu T, Ochiai H, Asell F, et al. Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19[J]. Drug Metab Pharmacokinet, 2003, 18(1):48-70.
8.	宋治, 何楠. CYP2C9/2C19基因多态性与苯妥英抗癫痫个体剂量差异的关系[J]. 神经疾病与精神卫生, 2002, 2(3):148-150.
9.	Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P4502C19 genetic polymorphism[J]. Clin Pharmacokinet, 2002, 41(12):913-958.
10.	Shu Y, Zhou HH. Individual and ethnic differences in CYP2C19 activity in Chinese populations[J]. Acta Pharmacol Sin, 2000, 21(3):193-199.
11.	Malfertheiner P, Mégraud F, O'morain C, et al. Current concepts in the management of Helicobacter pylori infection-the Maastricht 2-2000 Consensus Report[J]. Aliment Pharmacol Ther, 2002, 16(2):167-180.
12.	Sahara S, Sugimoto M, Uotani T, et al. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole[J]. Aliment Pharmacol Ther, 2013, 38(9):1129-1137.
13.	Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans[J]. Clin Pharmacol Ther, 1999, 65(5):552-561.
14.	Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH[J]. Aliment Pharmacol Ther, 2001, 15(12):1929-1937.
15.	Furuta T, Shirai N, Watanabe F, et al. Effect or cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole[J]. Clin Pharmacol Ther, 2002, 72(4):453-460.
16.	Furuta T, Shirai N, Takashima M, et al. Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin[J]. Pharmacogenetics, 2001, 11(4):341-348.
17.	Togawa J, Inamori M, Fujisawa N, et al. Efficacy of a triple therapy with rabeprazole, amoxicillin, and faropenem as second-line treatment after failure of initial Helicobacter pylori eradication therapy[J]. Hepatogastroenterology, 2005, 52(62):645-648.
18.	Furuta T, Shirai N, Takashima M, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin[J]. Clin Pharmacol Ther, 2001, 69(3):158-168.
19.	牛春燕, 罗金燕, 王学勤, 等. CYP2C19基因多态性对雷贝拉唑及埃索美拉唑抑酸效应的影响[J]. 中国临床医学, 2004, 11(6):1002-1004.
20.	Yamamoto Y, Takahashi Y, Imai K, et al. Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy[J]. Ther Drug Monit, 2013, 35(3):305-312.
21.	王育琴, 齐晓涟, 黄越, 等. 丙戊酸药物浓度与CYP2C19基因多态性关系的研究[J]. 中国医院药学杂志, 2003, 23(11):670-673.
22.	Van Der Weide J, Steijns LS, Van Weelden MJ, et al. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement[J]. Pharmacogenetics, 2001, 11(4):287-291.
23.	黄越, 齐晓涟, 王育琴, 等. CYP2C19基因型对丙戊酸及其与苯妥英联合用药时血药浓度影响[J]. 中国神经免疫学和神经病学杂志, 2003, 10(4):266-268, 275.
24.	Mrazek DA, Biernacka JM, O' kane DJ, et al. CYP2C19 variation and citalopram response[J]. Pharmacogenet Genomics, 2011, 21(1):1-9.
25.	Yu BN, Chen GL, He N, et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19[J]. Drug Metab Dispos, 2003, 31(10):1255-1259.
26.	Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes[J]. Br J Clin Pharmacol, 2003, 56(4):415-421.
27.	Montgomery SA, Huusom AK, Bothmer J. A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder[J]. Neuropsychobiology, 2004, 50(1):57-64.
28.	刘东波, 李淑英, 李泽华, 等. 细胞色素P450酶2C19基因多态性与艾司西酞普兰临床效应的关系[J]. 中国临床药理学杂志, 2013, 29(12):887-889.
29.	Gurbel PA, Cummings CC, Bell CR, et al. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting:the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial[J]. Am Heart J, 2003, 145(2):239-247.
30.	Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction[J]. Circulation, 2004, 109(25):3171-3175.
31.	Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement[J]. J Am Coll Cardiol, 2006, 48(9):1742-1750.
32.	Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events[J]. N Engl J Med, 2009, 360(4):363-375.
33.	Collet JP, Hulot JS, Pena AA, et al. Cytochrome P4502C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study[J]. Lancet, 2009, 373(9660):309-317.
34.	Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P4502C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis[J]. Am J Cardiol, 2009, 103(6):806-811.
35.	Trenk D, Hochholzer W, Frundi D, et al. Impact of cytochrome P4503A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement[J]. Thromb Haemost, 2008, 99(1):174-181.
36.	Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P4502C19681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents[J]. J Am Coll Cardiol, 2008, 51(20):1925-1934.
37.	Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel[J]. N Engl J Med, 2009, 360(4):354-362.
38.	Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use:a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents[J]. Circulation, 2008, 118(18):1894-1909.
39.	Ando Y, Fuse E, Figg WD. Thalidomide metabolism by the CYP2C subfamily[J]. Clin Cancer Res, 2002, 8(6):1964-1973.
40.	Li Y, Jiang Z, Xiao Y, et al. Metabolism of Thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma and antiangiogenic activities in vitro[J]. Hematol Oncol, 2012, 30(1):13-21.
41.	Li Y, Hou J, Wang D, et al. Prognostic factors for the efficacy of thalidomide in the treatment of multiple myeloma:a clinical study of 110 patients in China[J]. Leuk Lymphoma, 2006, 47(12):2593-2600.
42.	Nakamoto K, Kidd JR, Jenison RD, et al. Genotyping and haplotyping of CYP2C19 functional alleles on thin-film biosensor chips[J]. Pharmacogenet Genomics, 2007, 17(2):103-114.

1. Wroblewski B, Glenn MB. The cytochrome p-450 drug metabolizing enzyme system:an overview of potential clinically important drug interactions[J]. J Head Trauma Rehabil, 2002, 17(6):571-574.
2. Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P4502C19:correlation between 2C19 and S-mephenytoin 4'-hydroxylation[J]. Arch Biochem Biophys, 1993, 306(1):240-245.
3. He N, Yan FX, Huang SL, et al. CYP2C19 genotype and S-mephenytoin 4'-hydroxylation phenotype in a Chinese Dai population[J]. Eur J Clin Pharmacol, 2002, 58(1):15-18.
4. Finta C, Zaphiropoulos PG. The human CYP2C locus:a prototype for intergenic and exon repetition splicing events[J]. Genomics, 2000, 63(3):433-438.
5. De Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans[J]. J Biol Chem, 1994, 269(22):15419-15422.
6. De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese[J]. Mol Pharmacol, 1994, 46(4):594-598.
7. Shimizu T, Ochiai H, Asell F, et al. Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19[J]. Drug Metab Pharmacokinet, 2003, 18(1):48-70.
8. 宋治, 何楠. CYP2C9/2C19基因多态性与苯妥英抗癫痫个体剂量差异的关系[J]. 神经疾病与精神卫生, 2002, 2(3):148-150.
9. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P4502C19 genetic polymorphism[J]. Clin Pharmacokinet, 2002, 41(12):913-958.
10. Shu Y, Zhou HH. Individual and ethnic differences in CYP2C19 activity in Chinese populations[J]. Acta Pharmacol Sin, 2000, 21(3):193-199.
11. Malfertheiner P, Mégraud F, O'morain C, et al. Current concepts in the management of Helicobacter pylori infection-the Maastricht 2-2000 Consensus Report[J]. Aliment Pharmacol Ther, 2002, 16(2):167-180.
12. Sahara S, Sugimoto M, Uotani T, et al. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole[J]. Aliment Pharmacol Ther, 2013, 38(9):1129-1137.
13. Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans[J]. Clin Pharmacol Ther, 1999, 65(5):552-561.
14. Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH[J]. Aliment Pharmacol Ther, 2001, 15(12):1929-1937.
15. Furuta T, Shirai N, Watanabe F, et al. Effect or cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole[J]. Clin Pharmacol Ther, 2002, 72(4):453-460.
16. Furuta T, Shirai N, Takashima M, et al. Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin[J]. Pharmacogenetics, 2001, 11(4):341-348.
17. Togawa J, Inamori M, Fujisawa N, et al. Efficacy of a triple therapy with rabeprazole, amoxicillin, and faropenem as second-line treatment after failure of initial Helicobacter pylori eradication therapy[J]. Hepatogastroenterology, 2005, 52(62):645-648.
18. Furuta T, Shirai N, Takashima M, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin[J]. Clin Pharmacol Ther, 2001, 69(3):158-168.
19. 牛春燕, 罗金燕, 王学勤, 等. CYP2C19基因多态性对雷贝拉唑及埃索美拉唑抑酸效应的影响[J]. 中国临床医学, 2004, 11(6):1002-1004.
20. Yamamoto Y, Takahashi Y, Imai K, et al. Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy[J]. Ther Drug Monit, 2013, 35(3):305-312.
21. 王育琴, 齐晓涟, 黄越, 等. 丙戊酸药物浓度与CYP2C19基因多态性关系的研究[J]. 中国医院药学杂志, 2003, 23(11):670-673.
22. Van Der Weide J, Steijns LS, Van Weelden MJ, et al. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement[J]. Pharmacogenetics, 2001, 11(4):287-291.
23. 黄越, 齐晓涟, 王育琴, 等. CYP2C19基因型对丙戊酸及其与苯妥英联合用药时血药浓度影响[J]. 中国神经免疫学和神经病学杂志, 2003, 10(4):266-268, 275.
24. Mrazek DA, Biernacka JM, O' kane DJ, et al. CYP2C19 variation and citalopram response[J]. Pharmacogenet Genomics, 2011, 21(1):1-9.
25. Yu BN, Chen GL, He N, et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19[J]. Drug Metab Dispos, 2003, 31(10):1255-1259.
26. Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes[J]. Br J Clin Pharmacol, 2003, 56(4):415-421.
27. Montgomery SA, Huusom AK, Bothmer J. A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder[J]. Neuropsychobiology, 2004, 50(1):57-64.
28. 刘东波, 李淑英, 李泽华, 等. 细胞色素P450酶2C19基因多态性与艾司西酞普兰临床效应的关系[J]. 中国临床药理学杂志, 2013, 29(12):887-889.
29. Gurbel PA, Cummings CC, Bell CR, et al. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting:the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial[J]. Am Heart J, 2003, 145(2):239-247.
30. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction[J]. Circulation, 2004, 109(25):3171-3175.
31. Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement[J]. J Am Coll Cardiol, 2006, 48(9):1742-1750.
32. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events[J]. N Engl J Med, 2009, 360(4):363-375.
33. Collet JP, Hulot JS, Pena AA, et al. Cytochrome P4502C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study[J]. Lancet, 2009, 373(9660):309-317.
34. Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P4502C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis[J]. Am J Cardiol, 2009, 103(6):806-811.
35. Trenk D, Hochholzer W, Frundi D, et al. Impact of cytochrome P4503A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement[J]. Thromb Haemost, 2008, 99(1):174-181.
36. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P4502C19681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents[J]. J Am Coll Cardiol, 2008, 51(20):1925-1934.
37. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel[J]. N Engl J Med, 2009, 360(4):354-362.
38. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use:a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents[J]. Circulation, 2008, 118(18):1894-1909.
39. Ando Y, Fuse E, Figg WD. Thalidomide metabolism by the CYP2C subfamily[J]. Clin Cancer Res, 2002, 8(6):1964-1973.
40. Li Y, Jiang Z, Xiao Y, et al. Metabolism of Thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma and antiangiogenic activities in vitro[J]. Hematol Oncol, 2012, 30(1):13-21.
41. Li Y, Hou J, Wang D, et al. Prognostic factors for the efficacy of thalidomide in the treatment of multiple myeloma:a clinical study of 110 patients in China[J]. Leuk Lymphoma, 2006, 47(12):2593-2600.
42. Nakamoto K, Kidd JR, Jenison RD, et al. Genotyping and haplotyping of CYP2C19 functional alleles on thin-film biosensor chips[J]. Pharmacogenet Genomics, 2007, 17(2):103-114.

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CYP2C19基因多态性与个体化治疗的研究进展

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