Glutathione transferase-A2 s112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

Francesca Bonifazi, Gianluca Storci, Giuseppe Bandini, Elena Marasco, Elisa Dan, Elena Zani, Fiorenzo Albani, Sara Bertoni, Andrea Bontadini, Sabrina De Carolis, Maria Rosaria Sapienza, Simonetta Rizzi, Maria Rosa Motta, Martina Ferioli, Paolo Garagnani, Michele Cavo, Vilma Mantovani, Massimiliano Bonafè

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 languageEnglish
Pages (from-to)172-179
Number of pages8
JournalHaematologica
Volume99
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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Busulfan
Stem Cell Transplantation
Glutathione Transferase
Bilirubin
varespladib methyl
Transplants
Survival
Mortality
Glutathione
Liver
Organic Anion Transporters
NF-kappa B
Interleukin-8
Serine
Hepatocellular Carcinoma
Homeostasis
Down-Regulation
Alleles
Genotype
Inflammation

ASJC Scopus subject areas

  • Hematology

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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 journalArticle

Bonifazi, F, Storci, G, Bandini, G, Marasco, E, Dan, E, Zani, E, Albani, F, Bertoni, S, Bontadini, A, De Carolis, S, Sapienza, MR, Rizzi, S, Motta, MR, Ferioli, M, Garagnani, P, Cavo, M, Mantovani, V & Bonafè, M 2014, 'Glutathione transferase-A2 s112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation', Haematologica, vol. 99, no. 1, pp. 172-179. https://doi.org/10.3324/haematol.2013.089888
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. / Glutathione transferase-A2 s112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation. In: Haematologica. 2014 ; Vol. 99, No. 1. pp. 172-179.
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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

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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.

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