Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygenase-1

J Toxicol Sci. 2011 Oct;36(5):635-43. doi: 10.2131/jts.36.635.


Auranofin, a disease-modifying gold compound, has been empirically applying to the management of rheumatoid arthritis. We investigated a protective effect of auranofin against hepatic injury induced by cocaine. Cocaine (75 mg/kg) markedly increased serum alanine amino transferase (ALT) (4,130 IU/l) and aspartate amino transferase (AST) (1,730 IU/l) activities at 16 hr after treatment, and induced hepatic necrosis surrounding central veins in mice. Concurrently, overexpression of heme oxygenase-1 (HO-1), a rate-limiting enzyme for heme degradation and an oxidative stress marker, was identified at the edges of cocaine-mediated necrotic area. Auranofin (10 mg/ml, i.p.) significantly induced hepatic HO-1 protein in mice from 12 hr after treatment. Interestingly, pretreatment with auranofin resulted in the prevention of the increase of serum ALT and AST activities in a dose-dependent manner. On the other hand, although cocaine increased tumor necrosis factor α (TNFα) gene expression in mouse livers, cocaine-induced liver injury was observed in TNFα deficient mice as well as wild-type mice. Auranofin-inducted HO-1 gene expression was observed in human primary hepatocytes as well as mouse primary hepatocytes. The present findings suggest that auranofin is effective in preventing cocaine-induced hepatic injury, and HO-1 may contribute to protect against chemically-induced cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Auranofin / administration & dosage
  • Auranofin / therapeutic use*
  • Blotting, Northern
  • Blotting, Western
  • Cell Culture Techniques
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Cocaine / toxicity*
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Induction / drug effects
  • Heme Oxygenase-1 / biosynthesis*
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / pathology
  • Humans
  • Immunohistochemistry
  • Liver Function Tests
  • Male
  • Membrane Proteins / biosynthesis*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / pathology
  • Protective Agents / administration & dosage
  • Protective Agents / therapeutic use*
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology


  • Membrane Proteins
  • Protective Agents
  • Tumor Necrosis Factor-alpha
  • Auranofin
  • Cytochrome P-450 Enzyme System
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Cocaine