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

<b>Aims </b><br />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 <i>GSTM1</i>, <i>GSTT1</i>, and <i>GSTP1</i> genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE.<br /> <b>Methods</b><br />DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (<i>n</i> = 102). <i>GSTM1</i> and <i>GSTT1 </i>null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the <i>GSTP1</i> codon 105 polymorphism (Ile→Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay.<br /> <b>Results</b><br />Our study demonstrated that SLE patients carrying the genotypes with <i>GSTP1</i> codon 105 mutation [<i>GSTP1</i>*-105I/V (heterozygote) and <i>GSTP1</i>*-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 (<i>GSTP1</i>*I/V and <i>GSTP1</i>*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, <i>GSTM1 </i>and <i>GSTT1</i> null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients.<br /> <b>Conclusions</b><br />The <i>GSTP1</i> codon 105 polymorphism, but not <i>GSTM1</i> or <i>GSTT1</i> 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.<br />