Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation.
Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36 ± 570.06 vs. 838.10 ± 282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280 ± 0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.
francesca.bonifazi@unibo.it.
Francesca
F
Bonifazi
Gianluca
G
Storci
Giuseppe
G
Bandini
Elena
E
Marasco
Elisa
E
Dan
Elena
E
Zani
Fiorenzo
F
Albani
Sara
S
Bertoni
Andrea
A
Bontadini
Sabrina
S
De Carolis
Maria Rosaria
MR
Sapienza
Simonetta
S
Rizzi
Maria Rosa
MR
Motta
Martina
M
Ferioli
Paolo
P
Garagnani
Michele
M
Cavo
Vilma
V
Mantovani
Massimiliano
M
Bonafè
D000293:Adolescent; D000328:Adult; D001663:Bilirubin / Q000097:blood*; D002066:Busulfan / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012008:Recurrence; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D002066:Busulfan; D001663:Bilirubin