王憲剛 1,2 , 苗佳 1
  • 1 四川大學(xué)華西醫(yī)院臨床藥理研究所（成都，610041）;2 內(nèi)江市第一人民醫(yī)院;

【摘要】細(xì)胞色素酶P450 3A（cytochrome P450 3A，CYP3A）是人體代謝許多內(nèi)源性化合物、外源性底物及其前致癌物的一類重要的肝臟藥物氧化代謝酶，占成人肝臟細(xì)胞色素總量的30%，代謝超過50%的臨床用藥物。而CYP3A5是P450 3A家族中活性最強(qiáng)的酶之一，因存在突變多態(tài)性，不同的單核苷酸多態(tài)（single nucleotide polymorphism， SNP）可導(dǎo)致藥物有不同的代謝活性，對不同SNP的分析可以對個性化用藥做出指導(dǎo)。不同的SNP可能還與某些疾病的遺傳易感性相關(guān)，就上述CYP3A5的遺傳多態(tài)性及臨床意義進(jìn)行綜述。

引用本文： 王憲剛,苗佳. CYP3A5基因遺傳多態(tài)性及臨床研究進(jìn)展. 華西醫(yī)學(xué), 2010, 25(10): 1930-1933. doi: 復(fù)制

1. 呂水利, 黃英. 藥物代謝中的CYP3A基因[J]. 國外醫(yī)學(xué)?藥學(xué)分冊, 2001, 28(5): 307-308.
2. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4): 383-391.
3. Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450ⅢA5 (HLp3)[J]. Mol Pharmacol, 1990, 38(2): 207-213.
4. Lin YS, Dowling AL, Quigley SD, et al. Coregulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol, 2002, 62(1): 162-172.
5. Roy JN, Lajoie J, Zijenah LS, et al. CYP3A5 genetic polymorphisma in different ethnic populations [J]. Drug Metab Dispos, 2005, 33 (7): 884-887.
6. Jounaidi Y, Hyrailles V, Gervot L, et al. Detection of CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein [J]. Biochem Biophys Res Commun, 1996, 221(2): 466-470.
7. Li D, Zhang G, Lou Y, et al. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups [J]. J Clin Pharm Ther, 2007, 32: 89-95.
8. Lee SJ, van der Heiden IP, Goldstein JA, et al. A new CYP3A5 variant, CYP3A5*11, is shown to be defectivein nifedipine metabolism in a recombinant cDNA expression system [J]. Drug Metab Dispos, 2007, 35(1): 67-71.
9. Aulussen A, Larrijsen K, Bohets H, et al. Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determination of polymorphic activity in humans[J]. Pharma Cogenetics, 2000, 10: 415-424.
10. Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol. 2002, 62(1): 162-172.
11. Busi F, Cresteil T. CYP3A5 mRNA degradation by nonsense-mediated mRNA decay [J]. Mol Pharmacol, 2005, 68(3): 808-815.
12. Schuetz EG, Relling MV, Kishi S, et al. PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5 [J]. Pharmacol Rev, 2004, 56: 159.
13. Goetz MP, Toft D, Reid J, et al. Phase I trial of 17-allylamino-17-demethoxy-geldan-amycin in patients with advanced cancer[J]. J Clin Oncol, 2005, 23(6): 1078-1087.
14. Roninger E, Meeuwsen-de Boar T, Koopmans P, et al. Pharmacokinetics of vincristine monotherapy in childhood acute lymphoblastic leukemia[J]. Pediatr Res, 2002, 52(1): 113-118.
15. In YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and Intestinal midazolam metabolism [J]. Mol Pharmacol, 2002, 62: 162-172.
16. Haufroid V, Mourad M, van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients [J]. Pharmacogenetics, 2004, 14: 147-154.
17. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Geneticpolymorphisms of the CYP3A4, CYP3A5, and MDR21 genes and pharmacokinetics of the calcineur ininhibitors cyclosporine and tacrolimus [J]. Clin Pharm Acol Ther, 2003, 74: 245-254.
18. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 andMDR1 genetic polymor-phisms and cyclosporine pharamacokinetics after renal transplantation[J]. Clin Pharm Acol Ther, 2004, 75: 422-433.
19. Dennis A, Hesselink MD. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus [J]. Clin Pharm Acol Ther, 2003, 74: 245-254.
20. Zhang X, Liu Z, Zheng JM, et al. CYP3A5 andMDR1 gene polymorphisms is associated with pharmacokinetic variation of tacrolimus in renal transplant patients [J]. J Nephrol Dialy Transplant, 2004, 13: 59-64.
21. Wojnowski L, Turner PC, Pedersen B, et al. Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in the Gambia, West Africa [J]. Pharmacogenetics, 2004, 14: 691-700.
22. Dandara C, Ballo R, Parker MI, et al. CYP3A5 genotypes and risk of oesophageal cancer in two South African populations[J]. Cancer Lett, 2005, 225(2): 275-282.
23. 李振華, 孔垂?jié)? 王立忠. 前列腺癌發(fā)生風(fēng)險(xiǎn)與CYP3A5基因多態(tài)性的關(guān)系[J]. 中華實(shí)驗(yàn)外科雜志, 2003, 20(12): 1098-1099.
24. Plummer SJ, Conti DV, Paris PL, et al. CYP3A4 and CYP3A5 Genotypes, haplotypes, and risk of prostate cancer[J]. Cancer Epidemiol Biomarkers Prev, 2003, 12, 928-932.
25. Liu TC, Lin SF, Chen TP, et al. Polymorphism analysis of CYP3A5 in myeloid leukemia [J]. Oncol Rep, 2002, 9(2): 327-329.
26. Pakakasama S, Mukda E, Sasanakul W, et al. Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia [J]. Am J Hematol, 2005, 79(3): 202-205.
27. Nagai F, Hiyoshi Y, Sugimachi K, et al. Cytochrome P450 (CYP) expression in human myeloblastic and lymphoid cell lines [J]. Biol Pharm Bull, 2002, 25(3): 383-385.
28. Givens RC, Lin YS, Dowling AL, et al. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. [J]. Appl Physiol, 2003, 95: 1297-1300.
29. Herbert Ho, Amar Pinto, Stephen D, et al. Association between the CYP3A5 genotype and blood pressure[J]. Hypertension, 2005, 45: 294-298.
30. Scheen AJ. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide [J]. Clin Pharmacokinet, 2007, 46(2): 93-108.
  1. 1. 呂水利, 黃英. 藥物代謝中的CYP3A基因[J]. 國外醫(yī)學(xué)?藥學(xué)分冊, 2001, 28(5): 307-308.
  2. 2. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4): 383-391.
  3. 3. Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450ⅢA5 (HLp3)[J]. Mol Pharmacol, 1990, 38(2): 207-213.
  4. 4. Lin YS, Dowling AL, Quigley SD, et al. Coregulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol, 2002, 62(1): 162-172.
  5. 5. Roy JN, Lajoie J, Zijenah LS, et al. CYP3A5 genetic polymorphisma in different ethnic populations [J]. Drug Metab Dispos, 2005, 33 (7): 884-887.
  6. 6. Jounaidi Y, Hyrailles V, Gervot L, et al. Detection of CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein [J]. Biochem Biophys Res Commun, 1996, 221(2): 466-470.
  7. 7. Li D, Zhang G, Lou Y, et al. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups [J]. J Clin Pharm Ther, 2007, 32: 89-95.
  8. 8. Lee SJ, van der Heiden IP, Goldstein JA, et al. A new CYP3A5 variant, CYP3A5*11, is shown to be defectivein nifedipine metabolism in a recombinant cDNA expression system [J]. Drug Metab Dispos, 2007, 35(1): 67-71.
  9. 9. Aulussen A, Larrijsen K, Bohets H, et al. Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determination of polymorphic activity in humans[J]. Pharma Cogenetics, 2000, 10: 415-424.
  10. 10. Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism[J]. Mol Pharmacol. 2002, 62(1): 162-172.
  11. 11. Busi F, Cresteil T. CYP3A5 mRNA degradation by nonsense-mediated mRNA decay [J]. Mol Pharmacol, 2005, 68(3): 808-815.
  12. 12. Schuetz EG, Relling MV, Kishi S, et al. PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5 [J]. Pharmacol Rev, 2004, 56: 159.
  13. 13. Goetz MP, Toft D, Reid J, et al. Phase I trial of 17-allylamino-17-demethoxy-geldan-amycin in patients with advanced cancer[J]. J Clin Oncol, 2005, 23(6): 1078-1087.
  14. 14. Roninger E, Meeuwsen-de Boar T, Koopmans P, et al. Pharmacokinetics of vincristine monotherapy in childhood acute lymphoblastic leukemia[J]. Pediatr Res, 2002, 52(1): 113-118.
  15. 15. In YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and Intestinal midazolam metabolism [J]. Mol Pharmacol, 2002, 62: 162-172.
  16. 16. Haufroid V, Mourad M, van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients [J]. Pharmacogenetics, 2004, 14: 147-154.
  17. 17. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Geneticpolymorphisms of the CYP3A4, CYP3A5, and MDR21 genes and pharmacokinetics of the calcineur ininhibitors cyclosporine and tacrolimus [J]. Clin Pharm Acol Ther, 2003, 74: 245-254.
  18. 18. Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 andMDR1 genetic polymor-phisms and cyclosporine pharamacokinetics after renal transplantation[J]. Clin Pharm Acol Ther, 2004, 75: 422-433.
  19. 19. Dennis A, Hesselink MD. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus [J]. Clin Pharm Acol Ther, 2003, 74: 245-254.
  20. 20. Zhang X, Liu Z, Zheng JM, et al. CYP3A5 andMDR1 gene polymorphisms is associated with pharmacokinetic variation of tacrolimus in renal transplant patients [J]. J Nephrol Dialy Transplant, 2004, 13: 59-64.
  21. 21. Wojnowski L, Turner PC, Pedersen B, et al. Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in the Gambia, West Africa [J]. Pharmacogenetics, 2004, 14: 691-700.
  22. 22. Dandara C, Ballo R, Parker MI, et al. CYP3A5 genotypes and risk of oesophageal cancer in two South African populations[J]. Cancer Lett, 2005, 225(2): 275-282.
  23. 23. 李振華, 孔垂?jié)? 王立忠. 前列腺癌發(fā)生風(fēng)險(xiǎn)與CYP3A5基因多態(tài)性的關(guān)系[J]. 中華實(shí)驗(yàn)外科雜志, 2003, 20(12): 1098-1099.
  24. 24. Plummer SJ, Conti DV, Paris PL, et al. CYP3A4 and CYP3A5 Genotypes, haplotypes, and risk of prostate cancer[J]. Cancer Epidemiol Biomarkers Prev, 2003, 12, 928-932.
  25. 25. Liu TC, Lin SF, Chen TP, et al. Polymorphism analysis of CYP3A5 in myeloid leukemia [J]. Oncol Rep, 2002, 9(2): 327-329.
  26. 26. Pakakasama S, Mukda E, Sasanakul W, et al. Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia [J]. Am J Hematol, 2005, 79(3): 202-205.
  27. 27. Nagai F, Hiyoshi Y, Sugimachi K, et al. Cytochrome P450 (CYP) expression in human myeloblastic and lymphoid cell lines [J]. Biol Pharm Bull, 2002, 25(3): 383-385.
  28. 28. Givens RC, Lin YS, Dowling AL, et al. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. [J]. Appl Physiol, 2003, 95: 1297-1300.
  29. 29. Herbert Ho, Amar Pinto, Stephen D, et al. Association between the CYP3A5 genotype and blood pressure[J]. Hypertension, 2005, 45: 294-298.
  30. 30. Scheen AJ. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide [J]. Clin Pharmacokinet, 2007, 46(2): 93-108.