Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamide-based allogeneic hematopoietic stem cell transplantation.
THE AIM of this study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR-C677T, MTHFR-A1298C) and various glutathione S-transferases (GSTP1-Ilel05Val, GSTA1*a/b, GSTM1, GSTT1) on the occurrence of liver toxicity in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT).


METHODS
Eighty-four adult patients were enrolled in this retrospective study. All patients were treated with busulfan/cyclophosphamide as a conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. Genotyping was performed using PCR based restriction-fragment-length-polymorphism (RFLP) techniques.


RESULTS
Multivariate analysis identified the MTHFR-A1298C polymorphism as an independent predictor for maximum levels of bilirubin (p=0.0025) and duration of hyperbilirubinaemia (p=0.013). Furthermore, there was an association between this polymorphism and the occurrence of the sinusoidal obstruction syndrome (SOS) (p=0.048). No significant associations between the MTHFR-C677T or the various GST polymorphisms and liver toxicity were observed.


CONCLUSIONS
The MTHFR-A1298C polymorphism might be associated with liver toxicity in patients receiving allogeneic HSCT.
Goekkurt
Eray
E
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University Dresden, Germany. eray.goekkurt@uniklinikum-dresden.de
Stoehlmacher
Jan
J
Stueber
Christian
C
Wolschke
Christine
C
Eiermann
Thomas
T
Iacobelli
Simona
S
Zander
Axel R
AR
Ehninger
Gerhard
G
Kröger
Nicolaus
N
D000293:Adolescent; D000328:Adult; D002066:Busulfan / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury; D003520:Cyclophosphamide / Q000009:adverse effects*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000009:adverse effects*; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014184:Transplantation, Homologous
D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005982:Glutathione Transferase; D002066:Busulfan