Influence of Glutathione S Transferase A1 Gene Polymorphism (-69C > T, Rs3957356) on Intravenous Cyclophosphamide Efficacy and Side Effects: a Case-control Study in Egyptian Patients with Lupus Nephritis

Overview

Journal Clin Rheumatol

Publisher Springer

Specialty Rheumatology

Date 2020 Jul 15

PMID 32661806

Citations 7

Authors

Doaa H S Attia

Mervat Eissa

Lamees A Samy

Rasha A Khattab

Affiliations

Soon will be listed here.

Abstract

Objectives: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. Cyclophosphamide (CYC) is a cytotoxic drug of a narrow therapeutic window that is commonly used in lupus nephritis (LN) treatment. However, 30-40% of patients experience CYC resistance. CYC inactivation is mediated by the glutathione S transferases (GSTs) superfamily: GST class A (GSTA) has the greatest activity and contains 5 isoenzymes. Polymorphisms of genes involved in the drug metabolism could alter the drug pharmacokinetics and effectiveness. CYC pharmacokinetics and pharmacogenomics are extensively studied in malignancies; however, scarce data are available about this issue in the autoimmune rheumatic diseases. Prediction of the drug response helps the achievement of the highest benefit-to-risk ratio. The aim of this case-control study was to address the association between GSTA1 polymorphism (-69C > T, rs3957356), and the rate of response to and side effects of intravenous CYC in LN patients.

Methods: Ninety-four patients were included and divided into matched groups: resistant and responsive. Genotyping was performed using restriction fragment length polymorphism method after amplification.

Results: A significant association between the TT genotype, and CYC resistance and partial response was observed. Concerning the recessive model, none of the patients within the TT group achieved complete remission. CYC side effects were more common with the polymorphism under the genotype, recessive model, and allele distributions. When patients' pre- and post-treatment characteristics were compared, patients with the TT genotype did not show any significant improvement.

Conclusion: LN patients with GSTA1 (-69C > T, rs3957356) TT genotype have the highest risk of CYC unresponsiveness and toxicity. Key-Points • LN patients with the wild genotype of GSTA1 have the greatest probability of achieving a complete renal response to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of LN unresponsiveness to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of CYC-related side effects.

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References

Danchenko N, Satia J, Anthony M . Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006; 15(5):308-18. DOI: 10.1191/0961203306lu2305xx. View

Illei G, Austin H, Crane M, Collins L, Gourley M, Yarboro C . Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 2001; 135(4):248-57. DOI: 10.7326/0003-4819-135-4-200108210-00009. View

Steinberg A, Steinberg S . Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum. 1991; 34(8):945-50. DOI: 10.1002/art.1780340803. View

Boumpas D, Austin 3rd H, Vaughn E, Klippel J, Steinberg A, Yarboro C . Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet. 1992; 340(8822):741-5. DOI: 10.1016/0140-6736(92)92292-n. View

Mok C, Lau C, Wong R . Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum. 1998; 41(5):831-7. DOI: 10.1002/1529-0131(199805)41:5<831::AID-ART9>3.0.CO;2-1. View

Radis C, Kahl L, BAKER G, Wasko M, Cash J, Gallatin A . Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. Arthritis Rheum. 1995; 38(8):1120-7. DOI: 10.1002/art.1780380815. View

de Jonge M, Huitema A, Rodenhuis S, Beijnen J . Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005; 44(11):1135-64. DOI: 10.2165/00003088-200544110-00003. View

Wang H, Zhu X, Zhu Y, Xie Q, Lai L, Zhao M . The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients. Clin Immunol. 2015; 160(2):342-8. DOI: 10.1016/j.clim.2015.07.010. View

Dirven H, van Ommen B, van Bladeren P . Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res. 1994; 54(23):6215-20. View

10.

Hayes J, Flanagan J, Jowsey I . Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005; 45:51-88. DOI: 10.1146/annurev.pharmtox.45.120403.095857. View

11.

Hayes J, Strange R . Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000; 61(3):154-66. DOI: 10.1159/000028396. View

12.

Guthenberg C, Warholm M, Rane A, Mannervik B . Two distinct forms of glutathione transferase from human foetal liver. Purification and comparison with isoenzymes isolated from adult liver and placenta. Biochem J. 1986; 235(3):741-5. PMC: 1146750. DOI: 10.1042/bj2350741. View

13.

Mitchell A, Morin D, Lame M, Jones A . Purification, mass spectrometric characterization, and covalent modification of murine glutathione S-transferases. Chem Res Toxicol. 1995; 8(8):1054-62. DOI: 10.1021/tx00050a009. View

14.

Jemth P, STENBERG G, Chaga G, Mannervik B . Heterologous expression, purification and characterization of rat class theta glutathione transferase T2-2. Biochem J. 1996; 316 ( Pt 1):131-6. PMC: 1217312. DOI: 10.1042/bj3160131. View

15.

Black J, Litzow M, Hogan W, OKane D, Walker D, Lesnick T . Correlation of CYP2B6, CYP2C19, ABCC4 and SOD2 genotype with outcomes in allogeneic blood and marrow transplant patients. Leuk Res. 2011; 36(1):59-66. DOI: 10.1016/j.leukres.2011.06.020. View

16.

Sweeney C, Ambrosone C, Joseph L, Stone A, Hutchins L, Kadlubar F . Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment. Int J Cancer. 2003; 103(6):810-4. DOI: 10.1002/ijc.10896. View

17.

Yang G, Shu X, Ruan Z, Cai Q, Jin F, Gao Y . Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer. 2004; 103(1):52-8. DOI: 10.1002/cncr.20729. View

18.

Allan J, Wild C, Rollinson S, Willett E, Moorman A, Dovey G . Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci U S A. 2001; 98(20):11592-7. PMC: 58774. DOI: 10.1073/pnas.191211198. View

19.

Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld D . Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)--novel predictors for response and survival in gastric cancer patients. Br J Cancer. 2005; 94(2):281-6. PMC: 2361118. DOI: 10.1038/sj.bjc.6602891. View

20.

Beeghly A, Katsaros D, Chen H, Fracchioli S, Zhang Y, Massobrio M . Glutathione S-transferase polymorphisms and ovarian cancer treatment and survival. Gynecol Oncol. 2005; 100(2):330-7. DOI: 10.1016/j.ygyno.2005.08.035. View