title: The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation.
abstract: Cytochrome P450 enzymes (CYPs) and flavin-containing monooxygenases (FMOs) likely have a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro studies to investigate the involvement of these enzymes are cumbersome because of the volatile nature of the intermediate metabolite tetrahydrothiophene (THT) and the lack of sensitive quantitation methods. This study explored the association between the CYP2C9, CYP2C19, CYP2B6 and FMO3 genotypes and sulfolane (Su, a water soluble metabolite of Bu) plasma levels in children undergoing hematopoietic stem cell transplantation (HSCT). The relationship between these genotypes and the effectiveness of myeloablative conditioning was also analyzed. Sixty-six children receiving an intravenous Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). The plasma levels of Bu and its metabolite Su were measured after the ninth Bu dose in a subset of 44 patients for whom plasma samples were available. The ratio of Bu to Su was considered the metabolic ratio (MR) and was compared across the genotype groups. Higher MRs were observed in CYP2C9*2 and *3 allele carriers (mean±s.d.: 7.8±3.6 in carriers vs 4.4±2.2 in non-carriers; P=0.003). An increased incidence of graft failure was observed among patients with an MR>5 compared with those with MR values <5 (20% vs 0%; P=0.02). In contrast, a significantly higher incidence of relapse and graft failure (evaluated as event-free survival) was observed in patients with malignant disease who carried CYP2B6 alleles with reduced function on both chromosomes compared with carriers of at least one normal allele (100% vs 40%; P=0.0001). These results suggest that CYP2C9 has a role in the oxidation reactions of THT and indicate that it may be possible to predict the efficacy of Bu-based myeloablative conditioning before HSCT on the basis of CYP genotypes and Bu MRs.
authors.affiliation: 1] Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland [2] CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland.
authors.forename: C R S
authors.initials: CR
authors.lastname: Uppugunduri
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Rezgui
authors.affiliation: 1] Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland [2] CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland.
authors.forename: P H
authors.initials: PH
authors.lastname: Diaz
authors.affiliation: 1] Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland [2] CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland.
authors.forename: A K
authors.initials: AK
authors.lastname: Tyagi
authors.affiliation: Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: 1] CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland [2] Department of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Daali
authors.affiliation: 1] Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Duval
authors.affiliation: 1] Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Bittencourt
authors.affiliation: 1] Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [3] Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Krajinovic
authors.affiliation: 1] Department of Pediatrics, Onco-Hematology unit, University Hospital of Geneva, Geneva, Switzerland [2] CANSEARCH Research Laboratory, Geneva Medical University, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ansari
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002066:Busulfan / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011110:Polymorphism, Genetic; D013876:Thiophenes / Q000378:metabolism*; D019172:Transplantation Conditioning
chemical_list: D018906:Antineoplastic Agents, Alkylating; D013876:Thiophenes; D003577:Cytochrome P-450 Enzyme System; D002066:Busulfan; C013693:sulfolane