CYP3A4、CYP3A5 和CYP2D6 基因单核苷酸多态性对肾移植术后稳定期患者他克莫司代谢的影响

doi:10.3969/j.issn.1673-8640.2015.11.008

摘要/Abstract

摘要： 目的

探讨肾移植患者细胞色素P450 CYP3A4、CYP3A5 和CYP2D6 基因单核苷酸多态性与他克莫司(FK506)代谢的相关性以及根据基因多态性制定FK506个体化治疗方案的可行性。

方法

收集随访的138例肾移植稳定期患者,均采用含FK506、吗替麦考酚酯、糖皮质激素的三联治疗方案。记录单位体重用药剂量数据、FK506谷浓度和CYP3A4、CYP3A5、CYP2D6基因单核苷酸多态性测序法检测结果。分析单核苷酸多态性与浓度调整的单位体重用药剂量的相关性。

结果

在 138 例患者中, CYP3A4 野生型 TT等位基因频率为0.993、杂合子 TC等位基因频率为0.007;CYP3A5 野生型 AA等位基因频率为0.529、杂合子 AG等位基因频率为0.399、纯合子 GG等位基因频率为0.072;CYP2D6 野生型(76例)CC等位基因频率为0.550、杂合子 CT等位基因频率为0.449。为了达到相应的稳态浓度,CYP3A5 野生型(AA)患者与突变型(AG、GG)相比需要更高剂量的FK506 (P<0.001);而CYP2D6野生型(CC)和突变型(CT)之间FK506剂量差异无统计学意义(P>0.05)。

结论

CYP3A4 的基因多态性以野生型常见,对FK506代谢的影响较少。CYP3A5 的基因多态性与FK506的代谢密切相关,野生型患者需要较高剂量的FK506才能达到相应的稳态浓度。CYP2D6的基因多态性与FK506代谢无明显相关性。

关键词: 细胞色素P450, 肾移植, 他克莫司, 治疗药物监测

Abstract: Objective

To investigate the influence of cytochrome P450 CYP3A4, CYP3A5 and CYP2D6 single nucleotide polymorphism on tacrolimus (FK506) metabolism, and to study the feasibility of personalized base treatment of FK506.

Methods

A total of 138 renal transplantation patients during stable period were followed up. All patients received FK506, mycophenolate mofetil and prednisolone treatment. Drug dose per body weight was recorded, the trough concentration of FK506 was calculated, and gene sequencing was used to detect single nucleotide polymorphism of CYP3A4, CYP3A4 and CYP2D6. The drug dose per body weight of FK506 and its relationship with single nucleotide polymorphism were analyzed.

Results

Among the 138 patients genotyped for CYP3A4, 138 patients displayed wild type TT (allele frequency 0.993), heterozygous TC (0.007). There were CYP3A5 wild type AA (0.529), heterozygous AG (0.399) and homozygous GG (0.072 ). CYP2D6 showed 76 case of wild type CC (0.550) and heterozygous CT (0.449). Compared to heterozygous and homozygous alleles, CYP3A5 wild type (AA) and mutant type (AG and GG) expressed higher FK506 dose (P<0.001). CYP2D6 wild type (CC) and mutant type (CT) had no statistical significance with FK506 dose(P>0.05) .

Conclusions

The CYP3A4 genotype polymorphism is mainly wild type, and the significance for FK506 metabolism is minimal. CYP3A5 has a major role in FK506 metabolism, and the patients with wild type need high dose of FK506. The CYP2D6 polymorphism has no correlation with FK506 metabolism.

Key words: Cytochrome P450, Renal transplantation, Tacrolimus, Therapeutic drug monitoring

中图分类号:

Q503

周逸雯, 周琰, 吴炯, 鞠颖慧, 郭玮. CYP3A4、CYP3A5 和CYP2D6 基因单核苷酸多态性对肾移植术后稳定期患者他克莫司代谢的影响[J]. 检验医学, 2015, 30(11): 1091-1095.

ZHOU Yiwen, ZHOU Yan, WU Jiong, JU Yinghui, GUO Wei. The influence of CYP3A4, CYP3A5 and CYP2D6 single nucleotide polymorphism on tacrolimus metabolism in renal transplantation patients during stable period[J]. Laboratory Medicine, 2015, 30(11): 1091-1095.

图/表 3

参考文献 24

[1]	SAYEGH MH, CARPENTER CB.Transplantation 50 years later--progress, challenges, and promises[J]. N Engl J Med, 2004, 351(26): 2761-2766.
[2]	HALLORAN PF.Immunosuppressive drugs for kidney transplantation[J]. N Engl J Med, 2004,351(26): 2715-2729.
[3]	CLASE CM,MAHALATI K, KIBERD BA, et al.Adequate early cyclosporin exposure is critical to prevent renal allograft rejection: patients monitored by absorption profiling[J] . Am J Transplant, 2002, 2(8): 789-795.
[4]	UNDRE NA, VAN HOOFF J, CHRISTINANS M, et al.Low systemic exposure to tacrolimus correlates with acute rejection[J].Transplant Proc, 1999,31(1-2): 296-298.
[5]	NANKIVELL BJ, BORROWS RJ, FUNG CJ, et al.The natural history of chronic allograft nephropathy[J]. N Engl J Med, 2003,349(24): 2326-2333.
[6]	DAVIDSON JA, WILKINSON A, International Expert Panel on New-Onset Diabetes after Transplantation. New-onset diabetes after transplantation 2003 international consensus guidelines: an endocrinologist's view[J]. Diabetes Care, 2004, 27(3): 805-812.
[7]	DE JONGE H, NAESENS M, KUYPERS DR.New insights into the pharmacokinetics and pharmacody-namics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation[J]. Ther Drug Monit, 2009,31(4): 416-435.
[8]	HOLT DW.Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation[J]. Curr Opin Nephrol Hypertens, 2002, 11(6): 657-663.
[9]	DIAZ-MOLINA B, TAVIRA B, LAMBERT JL, et al.Effect of CYP3A5, CYP3A4, and ABCB1 genotypes as determinants of tacrolimus dose and clinical outcomes after heart transplantation[J]. Transplant Proc, 2012, 44(9):2635-2638.
[10]	PROVENZANI A, SANTEUSANIO A, MATHIS E, et al.Pharmacogenetic considerations for opti-mizing tacrolimus dosing in liver and kidney transplant patients[J]. World J Gastroenterol, 2013, 19(48): 9156-9173.
[11]	MIURA M, SATOH S, KAGAYA H, et al.Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients[J]. Pharmacogenomics, 2011,12(7):977-984.
[12]	BIRDWELL KA, GRADY B, CHOI L, et al.The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients[J]. Pharmacogenet Genomics, 2012, 22(1): 32-42.
[13]	FUKUSHIMA-UESAKA H, SAITO Y, WATANABE H, et al.Haplotypes of CYP3A4 and their close 24 linkage with CYP3A5 haplotypes in a Japanese population[J]. Hum Mutat, 2004, 23(1): 100.
[14]	MACPHEE IA, FREDERICKS S, MOHAMED M, et al.Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians[J]. Transplantation, 2005, 79(4): 499-502.
[15]	BARANSKA M, DZIANKOWSKA-BARTKOWIAK B, WASCZYKOWSKA E, et al.Significance of genetic polymorphism of CYP2D6 in the pathogenesis of systemic sclerosis[J]. Pharmacol Rep, 2012, 64(2): 336-342.
[16]	SOYAMA A, KUBO T, MIYAJIMA A, et al.Novel nonsynonymous single nucleotide polymorphisms in the CYP2D6 gene[J]. Drug Metab Pharmacokinet, 2004, 19(4): 313-319.
[17]	ZHOU SF.Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part Ⅰ[J]. Clin Pharmacokinet, 2009, 48(11): 689-723.
[18]	TEH LK, BERTILSSON L.Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance[J]. Drug Metab Pharmacokinet, 2012, 27(1): 55-67.
[19]	SUZUKI Y, FUKUI N, TSUNEYAMA N, et al.Effect of the cytochrome P450 2D6*10 allele on risperidone metabolism in Japanese psychiatric patients[J]. Hum Psychopharmacol, 2012, 27(1): 43-46.
[20]	BALL SE, SCATINA J, KAO J, et al.Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4[J]. Clin Pharmacol Ther, 1999, 66(3): 288-294.
[21]	燕贞,吴逸明,吴拥军. CYP2D6*10 多态性和肺癌易感性[J]. 中国医学科学院学报, 2008, 30(5):564-568.
[22]	GLOWACKI F, LIONET A, BUOB D, et al.CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation[J]. Nephrol Dial Transplant , 2011, 26(9): 3046-3050.
[23]	KURZAWSKI M, DABROWSKA J, DZIEWA-NOWSKI K, et al.CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipient[J].Pharmacogenomics,2014,15(2):179-188.
[24]	SAKUYAMA K, SASAKI T, UJIIE S, et al.Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57)[J]. Drug Metab Dispos, 2008, 36(12): 2460-2467.

基因型	前向引物(5'-3')	反向引物(5'-3')
CYP3A4*18B(20070T>C)(rs2242480)	CACCCTGATGTCCAGAAACT	AATAGAAAGCGATGAACCAGAGCC
CYP3A5*3(6986A>G)(rs776746)	TGTACCACCCAGCTTAACGA	ATTAAACTTCACTAGCCCGAT
CYP2D6*10(C188>T) (rs1065852)	CAACACAGCAGGTTCACTCACA	TGCTTCGACCAGGTGAGGGAG

基因型	前向引物(5'-3')	反向引物(5'-3')
CYP3A4*18B(20070T>C)(rs2242480)	CACCCTGATGTCCAGAAACT	AATAGAAAGCGATGAACCAGAGCC
CYP3A5*3(6986A>G)(rs776746)	TGTACCACCCAGCTTAACGA	ATTAAACTTCACTAGCCCGAT
CYP2D6*10(C188>T) (rs1065852)	CAACACAGCAGGTTCACTCACA	TGCTTCGACCAGGTGAGGGAG

基因	基因型	例数(频率)	P值
CYP3A4	TT	137 (0.993)	0.970
	TC	1 (0.007)
CYP3A5	AA	73(0.529)	0.935
	AG	55(0.399)
	GG	10(0.072)
CYP2D6	CC	76 (0.550)	0.126
	CT	62 (0.449)

基因	基因型	例数(频率)	P值
CYP3A4	TT	137 (0.993)	0.970
	TC	1 (0.007)
CYP3A5	AA	73(0.529)	0.935
	AG	55(0.399)
	GG	10(0.072)
CYP2D6	CC	76 (0.550)	0.126
	CT	62 (0.449)