Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

Sharda, Sheetal; Gulati, Sanjeev; Tripathi, Gaurav; Jafar, Tabrez; Kumar, Alok; Sharma, Raj Kumar; Agrawal, Suraksha

doi:10.1007/s00467-008-0883-1

Cited by 15 publications

(13 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that the total number of doses differed in treatment groups raises the question of whether equivalent doses (maybe given at different time intervals) may further improve results in the intravenous group. Sharda et al also reported a benefit in 50% of patients after intravenous cyclophosphamide, but they presented no exact outcome data [14]. Toxicity is reported to be less pronounced in the intravenous group so that further studies seem warranted.…”

Section: Levamisolementioning

confidence: 86%

“…Alternatively, younger children may have an immature immune system that responds differently to cytotoxic treatment. Also, certain genetic polymorphisms, such as glutathione-tranferase, may predict a better response to cytotoxic treatment [14]. More recently, Kyrileis et al [15] studied 93 children with SSNS and MCD from a biopsy registry with a median follow-up of 8 years (range 139 years).…”

Section: Levamisolementioning

confidence: 98%

See 1 more Smart Citation

New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome

2011

View full text Add to dashboard Cite

Although many children with idiopathic nephrotic syndrome (INS) respond initially to steroid therapy, repeated courses for patients with relapses often cause significant steroid toxicity. Patients with frequent relapses who develop steroid dependency thus require alternative treatment. The first such options have been considered to be cyclophosphamide or levamisole, although the latter is no longer available in many countries. There is also an increasing body of data indicating that mycophenolic acid (MPA) may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and often used after cytotoxic treatment, but long-term treatment with these agents is necessary, raising concerns of a possible accumulation of side effects. Some patients show a tendency to relapse even on such maintenance regimens, and some even have a refractory course that creates a medical dilemma. For this situation, recent data indicate that monoclonal antibodies directed to B-cells (e.g. rituximab) may have some effect and that such drugs may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to steroid treatment need genetic testing and a renal biopsy since focal segmental glomerulosclerosis (FSGS) may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors, mainly in the form of cyclosporine, but tacrolimus has also come into recent favor. Some studies have found cytotoxic treatment, especially intravenous cyclophosphamide, to be effective in steroid resistant nephrotic syndrome, but it seems to be inferior to calcineurin inhibitors. MPA and rituximab have also been used in children with primary FSGS, but the response seems to be inferior to that in patients with steroid sensitive nephrotic syndrome. Taken together, INS in both steroid-sensitive and steroid-resistant patients is a potentially complicated disorder, and despite a wide arsenal of immunological interventions, some patients have a treatment refractory course. Prospective studies or at least standardized treatment for complicated cases is urgently needed.

show abstract

Section: Levamisolementioning

confidence: 86%

Section: Levamisolementioning

confidence: 98%

New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome

2011

View full text Add to dashboard Cite

show abstract

“…The polymorphism associated with the highest risk (A313G) codes for the I104V residue that influences GSTP conjugation activity and in combination with a second polymorphic site, C341T → A113V, results in an allelic switch (i.e., IA to VV) that significantly alters GSTP activity toward specific substrates, including acrolein (Pal et al , 2000). Therefore, additional pharmacogenomic studies are required to determine whether GSTP polymorphisms also increase cardiac sensitivity to CY and whether the GSTP genotype could be used to identify patients that might be more sensitive to high-dose CY chemotherapy (Ekhart et al , 2008; Sharda et al , 2008). …”

Section: Discussionmentioning

confidence: 99%

“…Because of its immunosuppressive activity, it is also frequently used for the treating autoimmune diseases, amyloidosis, idiopathic nephritis, severe rheumatoid arthritis and multiple sclerosis (Perini et al , 2007; Sharda et al , 2008). Several of these treatment regimens require high doses of CY that are associated with significant side effects such as bone marrow suppression, and hemorrhagic cystitis that vary in incidence, manifestation and severity (Shepherd et al , 1991).…”

Section: Introductionmentioning

confidence: 99%

Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

Conklin

Haberzettl

Jagatheesan

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100-300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein-acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1-5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10-20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity.

show abstract

“…This further emphasizes the specific contribution of GSTP activity in the bladder; thus, despite being relatively enriched in total GST activity (i.e., GSTM), bladders of GSTP-null mice were highly sensitive to CY toxicity. GST isoforms other than GSTP may be involved in acrolein removal; for example, it has been reported that when hGSTP polymorphism (hGSTP105V) is combined with hGSTM1-null and hGSTT1-null genotypes, it increases steroid-dependent remission of idiopathic nephritic syndrome in children receiving intravenous CY (Sharda et al, 2008), suggesting that GST isoforms other than GSTP may also be involved in the detoxification of acrolein, although this remains to be quantitatively established.…”

Section: Discussionmentioning

confidence: 99%

Increased Sensitivity of GlutathioneS-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

Conklin¹,

Haberzettl²,

Lesgards³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Hemorrhagic cystitis and diffuse inflammation of the bladder, common side effects of cyclophosphamide (CY) treatment, have been linked to the generation of acrolein derived from CY metabolism. Metabolic removal of acrolein involves multiple pathways, which include reduction, oxidation, and conjugation with glutathione. Herein, we tested the hypothesis that glutathione S-transferase P (GSTP), the GST isoform that displays high catalytic efficiency with acrolein, protects against CYinduced urotoxicity by detoxifying acrolein. Treatment of wildtype (WT) and mGstP1/P2 null (GSTP-null) mice with CY caused hemorrhagic cystitis, edema, albumin extravasation, and sloughing of bladder epithelium; however, CY-induced bladder ulcerations of the lamina propria were more numerous and more severe in GSTP-null mice. CY treatment also led to greater accumulation of myeloperoxidase-positive cells and specific protein-acrolein adducts in the bladder of GSTP-null than WT mice. There was no difference in hepatic microsomal production of acrolein from CY or urinary hydroxypropyl mercapturic acid output between WT and GSTP-null mice, but CY induced greater c-Jun NH 2 -terminal kinase (JNK) and c-Jun, but not extracellular signal-regulated kinase or p38, activation in GSTP-null than in WT mice. Pretreatment with mesna (2-mercaptoethane sulfonate sodium) abolished CY toxicity and JNK activation in GSTP-null mice. Taken together, these data support the view that GSTP prevents CY-induced bladder toxicity, in part by detoxifying acrolein. Because polymorphisms in human GSTP gene code for protein variants differing significantly in their catalytic efficiency toward acrolein, it is likely that GSTP polymorphisms influence CY urotoxicity. In addition, pretreatment with dietary or nutrient inducers of GSTP may be of use in minimizing bladder injury in patients undergoing CY therapy.

show abstract

Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

Cited by 15 publications

References 15 publications

New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome

New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome

Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

Increased Sensitivity of GlutathioneS-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

Contact Info

Product

Resources

About