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 Blood, 1 September 2004, Vol. 104, No. 5, pp. 1574-1577.
Prepublished online as a Blood First Edition Paper on May 13, 2004; DOI 10.1182/blood-2003-11-3778.

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Submitted November 6, 2003
Accepted April 29, 2004

Glutathione S-Transferase M1 Polymorphism- A Risk Factor For Hepatic Venoocclusive Disease In Bone Marrow Transplantation

Alok Srivastava*, Balasubramanian Poonkuzhali, Ramachandran V Shaji, Biju George, Vikram Mathews, Mammen Chandy, and Rajagopal Krishnamoorthy

Department of Haematology, Christian Medical College, Vellore, Tamil Nadu, India
INSERM U 458, Hopital Robert Debre, Paris, France

* Corresponding author; email: aloks{at}cmcvellore.ac.in.

Hepatic veno-occlusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents especially busulfan and cyclophosphamide in the conditioning therapy. Busulfan as well as the metabolites of cyclophosphamide are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with {beta} thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with GSTM1 null genotype compared to those with GSTM1 positive genotype (46.5% vs 18.3%; p=0.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first dose steady state concentration was lower among those with HVOD (0.403±0.06 vs 0.33±0.071 L/h/kg; t-test p value= 0.00001 and 508+125 vs. 656+255 ng/ml, t-test p value= 0.001 respectively). We conclude that GSTM1 null genotype predisposes to HVOD and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of cellular GSH pool.


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