Abstract
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 busul-fan 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, mul-tidrug 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.
| Original language | English |
|---|---|
| Pages (from-to) | 172-179 |
| Number of pages | 8 |
| Journal | Haematologica |
| Volume | 99 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2014 |
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ASJC Scopus subject areas
- Hematology
Cite this
Glutathione transferase-A2 s112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation. / Bonifazi, Francesca; Storci, Gianluca; Bandini, Giuseppe; Marasco, Elena; Dan, Elisa; Zani, Elena; Albani, Fiorenzo; Bertoni, Sara; Bontadini, Andrea; De Carolis, Sabrina; Sapienza, Maria Rosaria; Rizzi, Simonetta; Motta, Maria Rosa; Ferioli, Martina; Garagnani, Paolo; Cavo, Michele; Mantovani, Vilma; Bonafè, Massimiliano.
In: Haematologica, Vol. 99, No. 1, 01.01.2014, p. 172-179.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Glutathione transferase-A2 s112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation
AU - Bonifazi, Francesca
AU - Storci, Gianluca
AU - Bandini, Giuseppe
AU - Marasco, Elena
AU - Dan, Elisa
AU - Zani, Elena
AU - Albani, Fiorenzo
AU - Bertoni, Sara
AU - Bontadini, Andrea
AU - De Carolis, Sabrina
AU - Sapienza, Maria Rosaria
AU - Rizzi, Simonetta
AU - Motta, Maria Rosa
AU - Ferioli, Martina
AU - Garagnani, Paolo
AU - Cavo, Michele
AU - Mantovani, Vilma
AU - Bonafè, Massimiliano
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 busul-fan 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, mul-tidrug 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.
AB - 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 busul-fan 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, mul-tidrug 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.
UR - http://www.scopus.com/inward/record.url?scp=84892588980&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892588980&partnerID=8YFLogxK
U2 - 10.3324/haematol.2013.089888
DO - 10.3324/haematol.2013.089888
M3 - Article
C2 - 24056816
AN - SCOPUS:84892588980
VL - 99
SP - 172
EP - 179
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 1
ER -