title: Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients.
abstract: BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (P ≤ 0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (P ≤ 0.03). Gene-dosage effect was also observed (P ≤ 0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P=0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P=0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P=0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.
authors.affiliation: Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ansari
authors.forename: M A
authors.initials: MA
authors.lastname: Rezgui
authors.forename: Y
authors.initials: Y
authors.lastname: Théoret
authors.forename: C R S
authors.initials: CR
authors.lastname: Uppugunduri
authors.forename: S
authors.initials: S
authors.lastname: Mezziani
authors.forename: M-F
authors.initials: MF
authors.lastname: Vachon
authors.forename: C
authors.initials: C
authors.lastname: Desjean
authors.forename: J
authors.initials: J
authors.lastname: Rousseau
authors.forename: M
authors.initials: M
authors.lastname: Labuda
authors.forename: C
authors.initials: C
authors.lastname: Przybyla
authors.forename: M
authors.initials: M
authors.lastname: Duval
authors.forename: M
authors.initials: M
authors.lastname: Champagne
authors.forename: C
authors.initials: C
authors.lastname: Peters
authors.forename: H
authors.initials: H
authors.lastname: Bittencourt
authors.forename: M
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D000328:Adult; D000367:Age Factors; D064591:Allografts; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D018628:Gene Dosage; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D019172:Transplantation Conditioning
chemical_list: D019653:Myeloablative Agonists; D005982:Glutathione Transferase; D002066:Busulfan