ABCC家族基因变异性研究进展

摘要/Abstract

摘要： ATP 结合盒亚家族C(ATP-Binding Cassette, Subfamily C, ABCC) 蛋白家族是新近发现的一个较大的蛋白家族。该家族目前由9 个成员所组成, 在人体内分布广泛, 参与机体内一些重要物质的转运。同时许多化疗药物也是它们的转运底物, 其过度表达往往与肿瘤的多药耐药密切相关。最新研究表明, ABCC 基因变异可以导致机体内物质代谢的改变和肿瘤耐药程度的改变, 有的甚至可以直接导致遗传性疾病的产生。本文对ABCC家族变异现象及其与肿瘤多药耐药的关系作一综述。

关键词: ABCC 家族, 基因变异, 多药耐药, 多态性

Abstract: The ABCC (ATP-Binding Cassette, Subfamily C, ABCC) family is a large protein family discovered recently. It is comprised of nine members which distribute widely in human body and participate in the transportion of many important substrates. Some chemotherapeutic agents are also substrates of ABCC whose over-expressions have been proved to be associated with multidrug resistance. Recently, some studies showed that some mutations of ABCC family could affect the substance metabolism and lead to tumor multidrug resistance, even result in genetic disorders. The genetic variants of the ABCC family and their association with tumor multidrug resistance were reviewed in this paper.

Key words: ABCC family, genovariation, multidrug resistance, polymorphism

中图分类号:

R730

尹继业, 刘昭前. ABCC家族基因变异性研究进展[J]. 中国临床药理学与治疗学, 2008, 13(2): 220-227.

YIN Ji-ye, LIU Zhao-qian. Research progress on gene variants of the ABCC family[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(2): 220-227.

参考文献

[1] Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene ina multidrug-resistant human lung cancer cell line[J]. Science, 1992, 258(5088):1650-1654.
[2] Letourneau IJ, Deeley RG, Cole SP. Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (ABCC1/ABCC1)[J]. Pharmacogenet Genomics, 2005, 15(9):647-657.
[3] Perdu J, Germain DP. Identification of novel polymorphisms in the pM5 and ABCC1 (ABCC1) genes at locus 16p13. 1 and exclusion of both genes as responsible for pseudoxanthoma elasticum[J]. Hum Mutat, 2001, 17(1): 74-75.
[4] Conrad S, Kauffmann HM, Ito K, et al. Identification of human multidrug resistance protein 1 (ABCC1) mutations and characterization of a G671V substitution[J]. J Hum Genet, 2001, 46(11):656-663.
[5] Conrad S, Kauffmann HM, Ito K, et al. A naturally occurring mutation in ABCC1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance[J]. Pharmacogenetics, 2002, 12(4):321-330.
[6] Ito S, Ieiri I, TanabeM, et al. Polymorphism of the ABC transporter genes, MDR1, ABCC1 and ABCC2/cMOAT, in healthy Japanese subjects[J]. Pharmacogenetics, 2001, 11(2):175-184.
[7] Saito S, IidaA, Sekine A, et al. Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/ABCC/CFTR)[J]. J Hum Genet, 2002, 47(4):147-171.
[8] Wang Z, Sew PH, Ambrose H, et al. Nucleotide sequence analyses of the ABCC1 gene in four populations suggest negative selection on its coding region[J]. BMC Genomics, 2006, 7:111.
[9] Wang H, Hao B, Zhou K, et al. Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population:implications for pharmacogenomic association studies[J]. Ann Hum Genet, 2004, 68(6):563-573.
[10] Nishioka C, Sakaeda T, Nakamura T, et al. MDR1, ABCC1 and ABCC2 genotypes and in vitro chemosensitivity in Japanese patients with colorectal adenocarcinomas[J]. Kobe J Med Sci, 2004, 50(5-6):181-188.
[11] Wojnowski L, Kulle B, Schirmer M, et al. NAD(P) H oxidase and multidrug resistance protein genetic polymor-phisms are associated with doxorubicin-induced cardiotoxicity[J]. Circulation, 2005, 112(24):3754-3762.
[12] Rau T, Erney B, Gores R, et al. High-dose methotrexate in pediatric acute lymphoblastic leukemia:impact of ABCC2 polymorphisms on plasma concentrations[J]. Clin Pharmacol Ther, 2006, 80(5):468-476.
[13] Itoda M, Saito Y, Soyama A, et al. Polymorphisms in the ABCC2 (cMOAT/ABCC2) gene found in 72 established cell lines derived from Japanese individuals:an association between single nucleotide polymorphisms in the 5'-untranslated region and exon 28[J]. Drug Metab Dispos, 2002, 30(4):363-364.
[14] de Jong FA, Scott-Horton TJ, Kroetz DL, et al. Irinotecan-induced diarrhea:functional significance of the polymorphic ABCC2 transporter protein[J]. Clin Pharmacol Ther, 2007, 81(1):42-49.
[15] Moriya Y, Nakamura T, Horinouchi M, et al. Effects of polymorphisms of MDR1, ABCC1, and ABCC2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects[J]. Biol Pharm Bull, 2002, 25(10):1356-1359.
[16] Hirouchi M, Suzuki H, Itoda M, et al. Characterization of the cellular localization, expression level, and function of SNP variants of ABCC2/ABCC2[J]. Pharm Res, 2004, 21(5):742-748.
[17] Hulot JS, Villard E, Maguy A, et al. A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination[J]. Pharmacogenet Genomics, 2005, 15(5):277-285.
[18] Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity:contribution of UGT2B7, CYP2C8, and ABCC2 genotypes[J]. Gastroenterology, 2007, 132(1):272-281.
[19] Naesens M, Kuypers DR, Verbeke K, et al. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients[J]. Transplantation, 2006, 82(8):1074-1084.
[20] Niemi M, Arnold KA, Backman JT, et al. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics[J]. Pharmacogenet Genomics, 2006, 16(11):801-808.
[21] Bernsdorf A, Giessmann T, Modess C, et al. Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms[J]. Br J Clin Pharmacol, 2006, 61(4):440-450.
[22] Machida I, Inagaki Y, Suzuki S, et al. Mutation analysis of the multidrug resistance protein 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome[J]. Hepatol Res, 2004, 30(2):86-90.
[23] Mor-Cohen R, Zivelin A, Rosenberg N, et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome[J]. J Biol Chem, 2001, 276(40):36923-36930.
[24] Wakusawa S, Machida I, Suzuki S, et al. Identification of a novel 2026G>C mutation of the ABCC2 gene in a Japanese patient with Dubin-Johnson syndrome[J]. J Hum Genet, 2003, 48(8):425-429.
[25] Tsujii H, Konig J, Rost D, et al. Exon-intron organization of the human multidrug-resistance protein 2 (ABCC2) gene mutated in Dubin-Johnson syndrome[J]. Gastroenterology, 1999, 117(3):653-660.
[26] Cebecauerova D, Jirasek T, Budisova L, et al. Dual hereditary jaundice:simultaneous occurrence of mutations causing Gilbert' s and Dubin-Johnson syndrome[J]. Gastroenterology, 2005, 129(1):315-320.
[27] Tate G, Li M, Suzuki T, et al. A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome[J]. Genes Genet Syst, 2002, 77(2):117-121.
[28] Materna V, Lage H. Homozygous mutation Arg768Trp in the ABC-transporter encoding gene ABCC2/cMOAT/ABCC2 causes Dubin-Johnson syndrome in a Caucasian patient[J]. J Hum Genet, 2003, 48(9):484-486.
[29] Izzedine H, Hulot JS, Villard E, et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy[J]. J Infect Dis, 2006, 194(11):1481-1491.
[30] Lang T, Hitzl M, Burk O, et al. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, ABCC3) gene and relationship to its mRNA and protein expression in human liver[J]. Pharmacogenetics, 2004, 14(3):155-164.
[31] Lee YM, Cui Y, Konig J, et al. Identification and functional characterization of the natural variant ABCC3-Arg1297His of human multidrug resistance protein 3 (ABCC3/ABCC3)[J]. Pharmacogenetics, 2004, 14(4):213-223.
[32] Eloranta ML, Heiskanen JT, Hiltunen MJ, et al. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis[J]. Eur J Obstet Gynecol Reprod Biol, 2002, 105(2):132-135.
[33] Doerfel C, Rump A, Sauerbrey A, et al. In acute leukemia, the polymorphism-211C>T in the promoter region of the multidrug resistance-associated protein 3 (ABCC3) does not determine the expression level of the gene[J]. Pharmacogenet Genomics, 2006, 16(2):149-150.
[34] Gradhand U, Tegude H, Burk O, et al. Functional analysis of the polymorphism-211C >T in the regulatory region of the human ABCC3 gene[J]. Life Sci, 2007, 80(16): 1490-1494.
[35] Gwee PC, Tang K, Sew PH, et al. Strong linkage disequilibrium at the nucleotide analogue transporter ABCC5 gene locus[J]. Pharmacogenet Genomics, 2005, 15(2): 91-104.
[36] Bergen AA, Plomp AS, Schuurman EJ, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum[J]. Nat Genet, 2000, 25(2):228-231.
[37] Uitto J, Pulkkinen L, Ringpfeil F. Molecular genetics of pseudoxanthoma elasticum:a metabolic disorder at the environment-genome interface[J]. Trends MolMed, 2001, 7(1):13-17.
[38] Ringpfeil F, Lebwohl MG, Christiano AM, et al. Pseudoxanthoma elasticum:mutations in the ABCC6 gene encoding a transmembrane ATP-binding cassette (ABC ) transporter[J]. Pro Nat Acad Sci, 2000, 97(11):6001-6006.
[39] Struk B, Cai L, Zach S, et al. Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum[J]. J Mol Med, 2000, 78(5):282-286.
[40] Kruh GD, Guo Y, Hopper-Borge E, et al. ABCC10, ABCC11, and ABCC12[J]. Pflugers Arch, 2007, 453(5): 675-684.