Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus

Zhong, Shilong, Huang, Min, Yang, Xiuyan, Liang, Liuqin, Wang, Yixi, Romkes, Marjorie, Duan, Wei, Chan, Eli and Zhou, Shu-Feng 2006, Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus, British journal of clinical pharmacology, vol. 62, no. 4, pp. 457-472.

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Title Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus
Author(s) Zhong, Shilong
Huang, Min
Yang, Xiuyan
Liang, Liuqin
Wang, Yixi
Romkes, Marjorie
Duan, Wei
Chan, Eli
Zhou, Shu-Feng
Journal name British journal of clinical pharmacology
Volume number 62
Issue number 4
Start page 457
End page 472
Publisher Blackwell Publishing Ltd.
Place of publication London, England
Publication date 2006-07-12
ISSN 0306-5251
Keyword(s) cyclophosphamide
glutathione S-transferase
single nucleotide polymorphism
systemic lupus erythematosus
toxicity
Summary Aims
Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE.
Methods
DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile→Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay.
Results
Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients.
Conclusions
The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.
Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009150

Document type: Journal Article
Collection: School of Medicine
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