International Urology and Nephrology

, Volume 44, Issue 1, pp 301–307 | Cite as

Glutathione S-transferases T1 null genotype is associated with susceptibility to aristolochic acid nephropathy

  • Bicheng Chen
  • Yongheng Bai
  • Mei Sun
  • Xiaojie Ni
  • Yunxiu Yang
  • Yirong Yang
  • Shaoling Zheng
  • Feifei Xu
  • Shengchuan Dai
Nephrology - Original Paper



This study aims to determine whether six polymorphisms of the genes involved in drug metabolism are associated with susceptibility to the development and progression of aristolochic acid nephropathy (AAN).


In the study, 91 aristolochic acid nephropathy (AAN) cases and 152 healthy controls of Chinese Han population were examined. Six common polymorphisms of genes, including multidrug resistance gene 1 (MDR1), cytochrome P450 (CYP1A1), NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) T1 and M1, were determined. Associations between their genotypes with AAN risk were calculated using an unconditional logistic regression model.


Among the six candidate polymorphisms, only the distribution frequency of GSTT1 null genotype was significantly higher among AAN cases compared with controls (P = 0.041, 62.6% vs. 48.7%) and was associated with a 1.7-fold increased risk (OR = 1.728, 95%CI: 1.013–2.948, P = 0.045) of developing AAN, after adjustment for age and gender. The stratified analysis further showed that the GSTT1 null genotype was dominant in slow progressive AAN patients (OR = 2.497, 95%CI: 1.028–6.064, P = 0.043). The GSTM1 genotypes were not shown to influence the development of AAN.


This study supports the hypothesis that polymorphisms related to drug metabolism such as GSTT1 may be an important factor influencing the development of AAN in the Chinese Han population exposed to AA.


Aristolochic acid nephropathy (AAN) Glutathione S-transferases T1 (GSTT1) Polymorphism 



We thank Elizabeth Barrington of the University of Pittsburgh for language correction. This study was sponsored by Zhejiang Provincial Top Key Discipline in Surgery and supported by the National Natural Science Foundation of China (Grant No. 30700768).


  1. 1.
    Vanherweghem JL, Depierreux M, Tielemans C et al (1993) Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341(8842):387–391PubMedCrossRefGoogle Scholar
  2. 2.
    Arlt VM, Stiborova M, Schmeiser HH (2002) Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17(4):265–277PubMedCrossRefGoogle Scholar
  3. 3.
    Cosyns JP (2003) Aristolochic acid and ‘Chinese herbs nephropathy’: a review of the evidence to date. Drug Saf 26(1):33–48PubMedCrossRefGoogle Scholar
  4. 4.
    Depierreux M, Van Damme B, Vanden Houte K et al (1994) Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 24(2):172–180PubMedGoogle Scholar
  5. 5.
    Chen W, Chen A, Li Y (2001) The clinical and pathological manifestations of aristolochic acid nephropathy–the report of 58 cases. Zhonghua Yi Xue Za Zhi 81(18):1101–1105PubMedGoogle Scholar
  6. 6.
    Tanaka A, Shinkai S, Kasuno K et al (1997) Chinese herbs nephropathy in the Kansai area: a warning report. Nippon Jinzo Gakkai Shi 39(4):438–440PubMedGoogle Scholar
  7. 7.
    Pawlik A, Baskiewicz-Masiuk M, Machalinski B et al (2005) Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. Eur J Pharmacol 528(1–3):27–36PubMedCrossRefGoogle Scholar
  8. 8.
    Xiao Y, Ge M, Xue X et al (2008) Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity. Kidney Int 73(11):1231–1239PubMedCrossRefGoogle Scholar
  9. 9.
    Radjendirane V, Joseph P, Lee YH et al (1998) Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J Biol Chem 273(13):7382–7389PubMedCrossRefGoogle Scholar
  10. 10.
    Goekkurt E, Al-Batran SE, Hartmann JT et al (2009) Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: a study of the arbeitsgemeinschaft internistische onkologie. J Clin Oncol 27(17):2863–2873PubMedCrossRefGoogle Scholar
  11. 11.
    Anwar-Mohamed A, Elbekai RH, El-Kadi AO (2009) Regulation of CYP1A1 by heavy metals and consequences for drug metabolism. Expert Opin Drug Metab Toxicol 5(5):501–521PubMedCrossRefGoogle Scholar
  12. 12.
    Brinkmann U, Roots I, Eichelbaum M (2001) Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 6(16):835–839PubMedCrossRefGoogle Scholar
  13. 13.
    Board PG (1980) Biochemical genetics of glutathione S2 transferase in man. Am J Hum Genet 33:36–43Google Scholar
  14. 14.
    Stiborova M, Frei E, Arlt VM et al (2009) The role of biotransformation enzymes in the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions and difficult answers. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 153(1):5–11PubMedGoogle Scholar
  15. 15.
    Stiborova M, Frei E, Arlt VM et al (2008) Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy. Mutat Res 658(1–2):55–67PubMedGoogle Scholar
  16. 16.
    Laing C, Hamour S, Sheaff M et al (2006) Chinese herbal uropathy and nephropathy. Lancet 368(9532):338PubMedCrossRefGoogle Scholar
  17. 17.
    Atsuta Y, Kawase H, Hamajima N et al (2005) Use of duplex PCR-CTPP methods for CYP2E1RsaI/IL-2 T-330G and IL-1B C-31T/TNF-A T-1031C polymorphisms. Mol Diagn 9(2):89–94PubMedCrossRefGoogle Scholar
  18. 18.
    Fu J, Yang YR, Ni XJ et al (2009) Establishment and preliminary application of polymerase chain reaction with confronting two-pair primers for the single nucleotide polymorphisms of metabolic enzymes. Zhonghua Liu Xing Bing Xue Za Zhi 30(1):63–67PubMedGoogle Scholar
  19. 19.
    Hamajima N (2001) PCR-CTPP: a new genotyping technique in the era of genetic epidemiology. Expert Rev Mol Diagn 1(1):119–123PubMedCrossRefGoogle Scholar
  20. 20.
    Farnsworth NR, Akerele O, Bingel AS et al (1985) Medicinal plants in therapy. Bull World Health Organ 63(6):965–981PubMedGoogle Scholar
  21. 21.
    Vanherweghem LJ (1998) Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy). J Altern Complement Med 4(1):9–13PubMedCrossRefGoogle Scholar
  22. 22.
    Swinney R, Hsu S, Tomlinson G (2006) Phase I and Phase II enzyme polymorphisms and childhood cancer. J Investig Med 54(6):303–320PubMedCrossRefGoogle Scholar
  23. 23.
    Brady JM, Cherrington NJ, Hartley DP et al (2002) Tissue distribution and chemical induction of multiple drug resistance genes in rats. Drug Metab Dispos 30(7):838–844PubMedCrossRefGoogle Scholar
  24. 24.
    Kiyohara C, Hirohata T, Inutsuka S (1996) The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene. Jpn J Cancer Res 87(1):18–24PubMedCrossRefGoogle Scholar
  25. 25.
    Lee KM, Kang D, Clapper ML et al (2008) CYP1A1, GSTM1, and GSTT1 polymorphisms, smoking, and lung cancer risk in a pooled analysis among Asian populations. Cancer Epidemiol Biomarkers Prev 17(5):1120–1126PubMedCrossRefGoogle Scholar
  26. 26.
    Grando JP, Kuasne H, Losi-Guembarovski R et al (2009) Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer. Clin Exp Med 9(1):21–28PubMedCrossRefGoogle Scholar
  27. 27.
    Toncheva DI, Von Ahsen N, Atanasova SY et al (2004) Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy. J Nephrol 17(3):384–389PubMedGoogle Scholar
  28. 28.
    Moran JL, Siegel D, Ross D (1999) A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Proc Natl Acad Sci U S A 96(14):8150–8155PubMedCrossRefGoogle Scholar
  29. 29.
    Chao C, Zhang ZF, Berthiller J et al (2006) NAD(P)H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15(5):979–987PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang ZP, Wang YR, Xu P et al (2008) Meta-analysis of the effect of MDR1 C3435T polymorphism on cyclosporine pharmacokinetics. Basic Clin Pharmacol Toxicol 103(5):433–444PubMedCrossRefGoogle Scholar
  31. 31.
    Wang BL, Zhai HY, Chen BY et al (2004) Clinical relationship between MDR1 gene and gallbladder cancer. Hepatobiliary Pancreat Dis Int 3(2):296–299PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, B.V. 2011

Authors and Affiliations

  • Bicheng Chen
    • 1
  • Yongheng Bai
    • 1
  • Mei Sun
    • 3
  • Xiaojie Ni
    • 2
  • Yunxiu Yang
    • 2
  • Yirong Yang
    • 2
  • Shaoling Zheng
    • 2
  • Feifei Xu
    • 3
  • Shengchuan Dai
    • 4
  1. 1.Wenzhou Key Laboratory of SurgeryThe First Affiliated Hospital of Wenzhou Medical CollegeWenzhouChina
  2. 2.Transplantation CentreThe First Affiliated Hospital of Wenzhou Medical CollegeWenzhouChina
  3. 3.Department of NephrologyThe First Affiliated Hospital of Wenzhou Medical CollegeWenzhouChina
  4. 4.Division of Cardiology, Cardiovascular InstituteUniversity of Pittsburgh Medical CenterPittsburghUSA

Personalised recommendations