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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.
TRANSPLANTATION Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantationFrom the Department of Haematology, Christian Medical College, Vellore, India; and Institut National de la Santé et de la Recherche Médicale (INSERM) U 458, Hopital Robert Debre, Paris, France.
Hepatic venoocclusive 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
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P = .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, Student t test P value = .000 01; and 508 ± 125 vs 656 ± 255 ng/mL, t test P value = .001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool. 
