Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia

Pharmacogenomics J. 2017 Jun;17(3):274-279. doi: 10.1038/tpj.2016.7. Epub 2016 Mar 29.


Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects*
  • Asparaginase / adverse effects*
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / pathology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Risk Assessment
  • Risk Factors
  • Superoxide Dismutase / genetics*
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Asparaginase