中国肾移植患者中细胞色素P450 3A4的新突变位点

doi:10.3969/j.issn.2095-4344.2013.05.005

中国组织工程研究 ›› 2013, Vol. 17 ›› Issue (5): 791-796.doi: 10.3969/j.issn.2095-4344.2013.05.005

• 肾移植 kidney transplantation • 上一篇下一篇

中国肾移植患者中细胞色素P450 3A4的新突变位点

石磊¹，贺宝霞¹, ²，曾晓晖¹，朱云松¹，张宏斌¹，保泽庆¹，赵树进¹

1 解放军广州军区广州总医院，广东省广州市 510010
2 河南省肿瘤医院药剂科, 河南省郑州市 450003

收稿日期:2012-05-02 修回日期:2012-06-14 出版日期:2013-01-29 发布日期:2013-01-29
通讯作者: 石磊,解放军广州军区广州总医院，广东省广州市 510010
作者简介:石磊★，女，汉族，河北省唐山市人，1962年生，1991年北京大学临床药理研究所毕业，硕士，主任药师，硕士生导师。

Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients

Shi Lei¹, He Bao-xia¹, ², Zeng Xiao-hui¹, Zhu Yun-song¹, Zhang Hong-bin¹, Bao Ze-qing¹, Zhao Shu-jin¹

1 Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, Guangdong Province, China
2 Department of Pharmacy, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China

Received:2012-05-02 Revised:2012-06-14 Online:2013-01-29 Published:2013-01-29
Contact: Shi Lei, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, Guangdong Province, China Lucyshi622.921@163.com
About author:Shi Lei★, Master, chief pharmacist, Master’s supervisor, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, Guangdong Province, China

摘要/Abstract

摘要：

背景：环孢素A在人体内主要经过细胞色素P450 3A4代谢。已有研究表明细胞色素P450 3A4基因多态性影响环孢素A的药代动力学，而且环孢素A慢性肾毒性主要是由于环孢素A在体内的长期蓄积。因此推测细胞色素P450 3A4基因多态性可能是肾移植移植后环孢素A 慢性肾毒性的主要原因之一。
目的：分析细胞色素P450 3A4基因多态性与肾移植移植后环孢素A 慢性肾毒性的相关性。
方法：纳入200例服用环孢素A的肾移植患者参加此项研究，其中105例经肾活检和(或)血肌酐值的变化诊断为环孢素A 慢性肾毒性，其他95例未发生肾毒性)。采集受试者外周静脉血并提取基因组DNA，采用聚合酶链式反应和直接测序法检测细胞色素P450 3A4基因外显子5，7，9和12的点突变。
结果与结论：中国肾移植患者中发现3个细胞色素P450 3A4新突变位点，即336 A>G，837 G>A 和406 A>C。其中 3例肾移植患者可检测出336 A>G，8例肾移植患者可检测出837 G>A。新突变点406 A>C仅发现于3例环孢素A慢性肾毒性患者，在非肾毒性患者中未发现新突变位点，且406 A>C可导致细胞色素P450 3A4保守区136位苏氨酸(Thr)转变为苯丙氨酸(Phe)。文章未发现已报道的中国人群细胞色素P450 3A4基因在外显子5，7，9和12的多态性。结果证实，文章在中国肾移植患者中发现了3个细胞色素P450 3A4的新突变位点336 A>G，837 G>A 和406 A>C，其中406 A>C可能引起细胞色素P450 3A4酶活性的改变。

关键词: 器官移植, 肾移植, 慢性肾毒性, 细胞色素P450 3A4, 环孢素A, 新突变, 省级基金

Abstract:

BACKGROUND: Cyclosporine A is metabolized mainly by cytochrome P450 3A4 (CYP3A4). Previous studies have suggested that genetic polymorphisms of CYP3A4 have an effect on the pharmacokinetics of cyclosporine A. Moreover, cyclosporine A -related chronic nephrotoxicity is caused by long-term exposure to cyclosporine A. It is conceivable that genetic polymorphisms of CYP3A4 may be responsible for the cyclosporine A-related chronic nephrotoxicity in renal transplant recipients.
OBJECTIVE: To analyze the relationship between CYP3A4 gene polymorphism and cyclosporine A- related chronic nephrotoxicity.
METHODS: A total of 200 patients (105 diagnosed as having cyclosporine A-related chronic renal toxicity through renal biopsy and (or) serum creatinine values change and 95 without nephrotoxicity) undergoing cyclosporine A therapy participated in this study. Peripheral venous blood samples were collected and genomic DNA was extracted. Mutations in exons 5, 7, 9, and 12 of the CYP3A4 gene were screened by PCR and direct DNA sequencing.
RESULTS AND CONCLUSION: Three novel mutations of CYP3A4 gene were discovered in this study, namely 336 A>G, 837 G>A and 406 A>C. The novel mutation 336 A>G was detected in three renal transplant recipients and 837 G>A was detected in eight recipients. Importantly, the novel mutation at 406A>C was detected only in three patients with cyclosporine A nephrotoxicity, and the novel mutation 406 A>C could result in the changes from 136 Threonine in the conserved region of CYP3A4 gene to phenylalanine. However, the known polymorphisms of exons 5, 7, 9, and 12 of the CYP3A4 gene were not detected in Chinese population. Three novel mutations at 336 A>G, 837 G>A and 406 A>C were detected in CYP3A4 gene in Chinese renal transplant recipients. The novel mutation at 406 A>C was predicted to change the enzyme activity of CYP3A4 enzyme.

Key words: organ transplantation, renal transplantation, chronic nephrotoxicity, cytochrome P450 3A4, cyclosporine A, new mutation, provincial grants-supported paper

中图分类号:

R318

石磊，贺宝霞，曾晓晖，朱云松，张宏斌，保泽庆，赵树进. 中国肾移植患者中细胞色素P450 3A4的新突变位点[J]. 中国组织工程研究, 2013, 17(5): 791-796.

Shi Lei, He Bao-xia, Zeng Xiao-hui, Zhu Yun-song, Zhang Hong-bin, Bao Ze-qing, Zhao Shu-jin. Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(5): 791-796.

图/表（结果） 5

参考文献

[1]      Fletcher JT, Nankivell BJ, Alexander SI. Chronic allograft nephropathy. Pediatr Nephrol. 2009;24(8):1465-1471.

[2]      Morales JM, Wramner L, Kreis H, et al. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant. 2002;2(5): 436-442.

[3]      Roy MK, Takenaka M, Kobori M, et al. Apoptosis, necrosis and cell proliferation-inhibition by cyclosporine A in U937 cells (a human monocytic cell line). Pharmacol Res. 2006; 53(3):293-302.

[4]      Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care. 2001;7(6):384-389.

[5]      Du J, Xing Q, Xu L, et al. Systematic screening for polymorphisms in the CYP3A4 gene in the Chinese population. Pharmacogenomics. 2006;7(6):831-841.

[6]      Ellouk-Achard S, Martin C, Pham-Huy C, et al. Implication of CYP 3A in the toxicity of cyclosporin G (CsG), cyclosporin A (Cyclosporine A) and FK506 on rat hepatocytes in primary culture. Arch Toxicol. 1997;71(7):437-442.

[7]      Sarah C Sim. Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee.

[8]      Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther. 2000;67(1):48-56.

[9]      Hsieh KP, Lin YY, Cheng CL, et al. Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001;29(3): 268-273.

[10]    Lamba JK, Lin YS, Thummel K, et al. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics. 2002;12(2): 121-132.

[11]    Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 2001; 299(3):825-831.

[12]    Hauser IA, Schaeffeler E, Gauer S, et al. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J Am Soc Nephrol. 2005;16(5):1501-1511.

[13]    Kelly P, Kahan BD. Review: Metabolism of immunosuppressant drugs. Curr Drug Metab. 2002;3(3): 275-287.

[14]    Min DI, Ellingrod VL. Association of the CYP3A4*1B 5’-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit. 2003;25(3):305-309.

[15]    Qiu XY, Jiao Z, Zhang M, et al. Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients. Eur J Clin Pharmacol. 2008;64(11):1069-1084.

[16]    Hu YF, Qiu W, Liu ZQ, et al. Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol P. 2006;33(11):1093-1098.

[17]    Gallon L, Akalin E, Lynch P, et al. ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients. Transplantation. 2006;81(3):463-468.

[18]    Smith HE, Jones JP 3rd, Kalhorn TF, et al. Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease. Pharmacogenet Genom. 2008;18(11):943-953.

[19]    Hawwa AF, McKiernan PJ, Shields M, et al Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol. 2009;68(3):413-421.

[20]    Kuypers DR, de Jonge H, Naesens M, et al CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther. 2007; 82(6):711-725.

[21]    Shi L, Bao Z, Zhu Y, et al. Correlation between CYP3A5 genetic polymorphism and calcineurin inhibitor-induced chronic nephrotoxicity following renal transplantation. Zhongguo Zuzhi Gongcheng Yanjiu yu Linchuang Kangfu. 2011;15(5):806-809.

[22]    Zhou Q, Yu X, Shu C, et al. Analysis of CYP3A4 genetic polymorphisms in Han Chinese. J Hum Genet. 2011;56(6): 415-422.

[23]    Eiselt R, Domanski TL, Zibat A, et al. Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics. 2001;11(5):447-458.

[24]    State Council of the People's Republic of China. Administrative Regulations on Medical Institution. 1994-09-01.

引言

Cyclosporine A, a member of the calcineurin inhibitor family, has been widely used to prevent the allograft rejection in solid organ transplantation recipients. It is particularly effective in improving 1-year renal allograft survival rate. However, long-term exposure to cyclosporine A may result in cyclosporine A nephrotoxicity, which is thought to be the major side effect of cyclosporine A. Moreover, therapeutic drug monitoring of cyclosporine A cannot prevent the eventual development of chronic nephrotoxicity in patients (30%-40%)^[1]. Thus, the identification of the risk factors of cyclosporine A-related chronic nephrotoxicity would be the great clinical significance which could help to improve the treatment of recipients.

There are two different forms of cyclosporine A nephrotoxicity^[2]. Acute nephrotoxicity, which is reversible, is a result of reduced renal blood flow. Several factors such as an increasing in thromboxane A2, a decreasing in prostaglandin E2, and the activation of endothelin-1 and the rennin-angiotensin system, are known to be involved in acute nephrotoxicity. Chronic nephrotoxicity, which is irreversible, is caused by long-term exposure to cyclosporine A. A direct cytotoxic effect of cyclosporine A ^[3], transforming growth factor-β and P-glycoprotein has been reported to be involved in this toxic response^[4]. Cyclosporine A is primarily metabolized by cytochrome P450 enzymes (CYP) 3A4 and 3A5, and is substrate for P-glycoprotein, an energy-dependent transmembrane efflux pump (ATP-binding cassette B1) encoded by the multidrug resistance 1 gene, also known as ABCB1. Interindividual variations in the expression and function of CYP3A4 and CYP3A5 are mainly caused by single-nucleotide polymorphisms of genes encoding these proteins^[5]. Several studies have shown that genetic polymorphisms of CYP3A4, CYP3A5, and multidrug resistance 1 contribute to inter- and intra-individual differences in the pharmacokinetics of cyclosporine A. Moreover, the toxicity of cyclosporine A decreased when CYP3A induced by dexamethasone^[6]. However, few studies have evaluated the relationship between polymorphisms of CYP3A4 and cyclosporine A-related nephrotoxicity.

Recently, a number of single-nucleotide polymorphisms of CYP3A4 have been identified^[7]. A total of 20 single-nucleotide polymorphisms of CYP3A4, including CYP3A4*1B, *1G, *3, *4, *5, *6, *8, *16, *17, and *18B, have been identified in Chinese population^[5]. However, only a few of these polymorphisms correlate with the changes of enzyme activity. CYP3A4*3, *4, *5, and *6 firstly found in the Chinese population and their frequencies are 1.5%, 1.5%, 0.98% and 0.5%, respectively^[8-9]. Moreover, CYP3A4*4, *5, *6, *16 and *17 have been known to down-regulate the enzyme activity of CYP3A^[9-11].

This retrospective study aimed to investigate the impact of CYP3A4 polymorphisms on the development of cyclosporine A-related chronic nephrotoxicity in Chinese renal transplant recipients.

材料方法

Design
A case control experiment.
Time and setting
The research was done between January 2008 and May 2010. The study was finished in the Medical Research Center and Department of Pharmacy, Guangzhou General Hospital of Guangzhou Military Command.
Subjects
A total of 200 renal transplant patients, including 105 patients diagnosed with cyclosporine A-related chronic nephrotoxicity and 95 patients without nephrotoxicity from the Guangzhou General Hospital of Guangzhou Military Command were recruited in the present study. The patients underwent transplantation between January 2001 and August 2007, and received a triple immunosuppressive regimen consisting cyclosporine A, mycophenolate mofetil and corticosteroids for at least 1 year. Patients aged 25-65 years were enrolled in the study. Cyclosporine A chronic nephrotoxicity was defined by biopsy-proven cyclosporine A-related nephrotoxicity or defined as described by Hauser et al ^[12]: serum creatinine level ≥1.6 mg/dL and ≤4.5 mg/dL over a period of 3 months and/or a creeping serum creatinine of approximately 20% from baseline; subsequent decreasing of serum creatinine to baseline status within a period of at most 6 months after conversion to a calcineurin inhibitor-free immunosuppression. Patients with acute rejection (judged by clinical evaluation using standard criteria such as acute rise in serum creatinine), gastrointestinal disorders and diabetes mellitus were excluded from the study. Patients with documented addiction to any known drug, nicotine, or alcohol were also excluded from this study.
Methods
Genotyping of CYP3A4 polymorphisms
Genomic DNA was isolated from the whole blood by using the Genomic DNA Blood Kit (Shanghai Sangon Biological Engineering Technology&Service Co., China). The DNA fragment containing the polymorphic site was amplified by PCR using the forward primer and the reverse primer (Table 1, Invitrogen, Shanghai, China). The PCR mix was 25 μL containing 2.5 μL 10×PCR buffer (Mg²⁺ plus), 50 pmol of each primer, 0.2 mmol/L of each deoxynucleotide triphosphate (dNTP), 2 UTaq deoxynucleic acid polymerase (TaKaRa Biotechnology Co., Ltd., Dalian, China) and 100 ng genomic DNA. Amplification conditions involved an initial denaturation at 94℃ for 7 minutes, followed by 35 cycles of 30 seconds at 94 ℃, 1 minuteat the anneal temperature (Table 1) and 1 minute at 72 ℃, with a final extension at 72 ℃ for 5 minutes. The PCR products were used for DNA sequencing.

Statistical analysis
Statistical analysis was performed with the SPSS 13.0 software package (SPSS, Chicago, IL, USA). Differences of continuous variables with normal distribution (presented as mean±SD) between two groups were calculated by an independent-sample t test. Differences of continuous variables departing from the normal distribution even after transformation between two groups were tested by Mann-Whitney U-test. Allelic frequencies were compared by using Fisher’s exact test. And Pearson’s chi-square test was used for Hardy-Weinberg equilibrium. Two-tailed P < 0.05 was considered as statistical significance.

讨论

In the present study, three novel mutations were detected in CYP3A4 gene in Chinese renal transplant recipients. The CYP3A subfamily is involved in the metabolism of approximately 50% of drugs, such as tacrolimus and cyclosporine A. The CYP3A subfamily consists of various isozymes, including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Cyclosporine A is primarily metabolized by CYP3A4 and CYP3A5 in the liver and small intestine. Cyclosporine A has three main cyclosporine A metabolites, AM1 (hydroxylation at aminoacid 1), AM9 (hydroxylation at amino acid 9), and AM4 (N-demethylation at amino acid 4), which were produced by CYP3A4; only the AM9 metabolite was formed by CYP3A5^[13]. Differences in CYP3A activity contribute greatly to variations in pharmacokinetics, responses, and toxicity of CYP3A substrates. Therefore, the genetic polymorphisms of CYP3A4 may play a major role in the interindividual differences of cyclosporine A pharmacokinetics and cyclosporine A-related nephrotoxicity.

One severe side effect of calcineurin inhibitors, including cyclosporine A and Tacrolimus, is nephrotoxicity. Recently, many studies have shown that genetic polymorphisms are associated with the variance of cyclosporine A pharmacokinetics. CYP3A4*1B is associated with the lower mean area under the plasma concentration-time curve/D (ng.hr/mL/mg) of cyclosporine A in healthy subjects^[14]. CYP3A4*18B and CYP3A5*3 genotypes have an effect on cyclosporine A pharmacokinetics during the first month after renal transplantation in Chinese recipients^[15-16]. The association of genetic polymorphisms with cyclosporine A-related nephrotoxicity has also been reported. Liver transplant recipients with angiotensin-converting enzyme gene D/D genotype have a significantly higher risk of developing calcineurin inhibitor-related chronic nephrotoxicity^[17]. Patients who are CYP2C8*3 carriers also have a higher risk of developing tacrolimus-related chronic nephrotoxicity, possibly because of the reduced formation of kidney-protecting vasodilatory epoxyeicosatrienoic acids^[18]. The donor’s ABCB1 genotype has been identified to play a dominant role in the development of cyclosporine A nephrotoxicity, and the reason is that low expression of P-glycoprotein in individual renal grafts leads to insufficient clearance of cyclosporine A^[12]. Another finding suggested that the ABCB1 polymorphisms in paediatric liver transplant recipients may contribute to nephrotoxicity over the first year after transplantation^[19]. Kuypers et al reported that CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes, but not multidrug resistance 1, in the recipients were associated with tacrolimus-related nephrotoxicity in renal transplant recipients; the higher systemic or tissue concentrations of toxic metabolites possibly resulted from CYP3A enzymes induced genetically (single-nucleotide polymorphisms) and non-genetically (corticosteroids)^[20]. Besides, in the previous study, polymorphisms of CYP3A5 were found to be significantly associated with the risk of calcineurin inhibitor drug-induced chronic nephrotoxicity^[21]. However, whether polymorphisms of CYP3A4*3, *4, *5, and *6 associated with cyclosporine A-related nephrotoxicity is still unclear.

A total of 200 Chinese renal transplant recipients undergoing cyclosporine A therapy participated in this study. The known alleles CYP3A4*3, *4, *5, *6, *8, *16, *17 were not found. However, three novel mutations were first detected in Chinese renal transplant recipients and all of these mutations were heterozygous. It is interesting that these mutations were not exist in the healthy Han Chinese^{[5, 22]}. The novel 366 A>G substitution in exon 5 was detected in one out of 105 patients with nephrotoxicity (0.95%) and two out of 95 patients without nephrotoxicity (2.11%). The novel 837 G>A substitution in exon 9 was detected in four out of 105 recipients with nephrotoxicity (3.81%) and four recipients without nephrotoxicity (4.21%). No significant differences existed in genotype frequencies between patients with nephrotoxicity and without nephrotoxicity (as shown in Table 4). The most interesting finding was that the point mutation 406 A>C in exon 5 was detected only in three patients with nephrotoxicity, which implied that the mutation may be associated with cyclosporine A- related chronic nephrotoxicity in renal transplant recipients. Although there were no significant differences between two groups and it is still unclear whether these mutations result in altered enzyme activity in vivo, it should be noted that the amino acid change from Thr to Phe at site 136 is highly conserved. Furthermore, the Thr136 follows Arg130, and Arg130 plays a dominant role in protein stabilization and heme binding^[23]. Thus, the 406 A>C probably damages the three-dimensional structure of the CYP3A4 enzyme (predicted through http://www. ebi.ac.uk/embl_services/#pro_pol) and alters the activity of CYP3A4. It will be necessary to assess the effect of 406 A>C on the activity of CYP3A4 enzyme in vivo.

In conclusion, we found three novel variants of CYP3A4 in Chinese renal transplant recipients. Further studies will be required to explore the prevalence of these mutations in other ethnic groups.

中国肾移植患者中细胞色素P450 3A4的新突变位点

Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

图/表（结果） 5

参考文献

相关文章 15

引言

材料方法

讨论

文章快阅

延伸阅读

编辑推荐

Metrics

本文评价

[1]	蒋欣, 乔良伟, 孙东, 李明, 房军, 曲青山. 肾移植患者血清中长链非编码RNA PGM5-AS1表达及调控人肾小球内皮细胞的作用[J]. 中国组织工程研究, 2021, 25(5): 741-745.
[2]	杨鑫, 金喆, 冯旭, 卢兵. 沈阳市居民对器官、眼组织及遗体捐献的认知及意愿调查[J]. 中国组织工程研究, 2021, 25(5): 779-784.
[3]	王晓勃, 王长安, 韩健乐, 杨青彦, 杨帅平, 杨俊伟. 环孢素转换为他克莫司对稳定期肾移植受者糖代谢和心血管风险的影响[J]. 中国组织工程研究, 2021, 25(14): 2236-2240.
[4]	刘君昌, 高小林, 姜泰茂. CYP3A5基因多态性与肾移植受者他克莫司浓度/剂量的关系及个体化用药[J]. 中国组织工程研究, 2021, 25(11): 1740-1744.
[5]	郭娟, 郑珊, 谢辉, 胡亚会. 肾移植受者422例病原菌感染分析[J]. 中国组织工程研究, 2020, 24(32): 5198-5202.
[6]	蔡秋程，范洪凯，熊日晖，江艺. 骨髓间充质干细胞对心脏死亡脂肪变供肝移植后肝功能的保护[J]. 中国组织工程研究, 2019, 23(17): 2625-2629.
[7]	杨进，张美霞，闫沛，程乔，李建珍. 肾移植后新发糖尿病危险因素的Meta分析[J]. 中国组织工程研究, 2019, 23(15): 2450-2460.
[8]	蒋珊珊，王峰，余丽梅. 间充质干细胞免疫调节特性及在器官移植中的应用[J]. 中国组织工程研究, 2019, 23(1): 103-109.
[9]	杨其顺，姜伟，黄赤兵 . 肾移植后肺部感染分期诊治：可提高肾移植后功能的稳定率[J]. 中国组织工程研究, 2018, 22(8): 1255-1260.
[10]	陈敏，许丽疆，翁景宁，上官晓辉，严俊，黄金棋，陈丹娜. 环孢素A微乳巴布膏眼贴的制备及体外透皮实验[J]. 中国组织工程研究, 2018, 22(10): 1553-1558.
[11]	尚文俊，王志刚，索敬钧，李金锋，庞新路，丰永花，刘磊，谢红昌，丰贵文. 公民逝世后器官捐献供肾移植术后应用卡泊芬净预防真菌感染的前瞻性研究[J]. 中国组织工程研究, 2017, 21(32): 5189-5196.
[12]	杨进，方芳，杨富. 肾移植术后新发糖尿病：危险因素的回顾性分析[J]. 中国组织工程研究, 2017, 21(20): 3275-3280.
[13]	李金锋，孙佳佳，丰贵文，尚文俊，庞新路，刘磊，谢红昌，丰永花，王志刚. 供、受者性别因素对公民逝世器官捐献供肾移植后肾功能恢复的影响[J]. 中国组织工程研究, 2017, 21(16): 2593-2599.
[14]	童灵犀，张传森，黄飞. 组织工程窦房结构建及血管化的最新研究与应用进展[J]. 中国组织工程研究, 2017, 21(16): 2606-2611.
[15]	赵敏，李秀芬. 骨髓间充质干细胞调节心脏移植大鼠的免疫功能[J]. 中国组织工程研究, 2016, 20(50): 7494-7499.