Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygenase-1.
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.
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. ashino@pharm.showa-u.ac.jp
Takashi
T
Ashino
Jinko
J
Sugiuchi
Junna
J
Uehara
Yumiko
Y
Naito-Yamamoto
Sachiyo
S
Kenmotsu
Yoichiro
Y
Iwakura
Seiji
S
Shioda
Satoshi
S
Numazawa
Takemi
T
Yoshida
D000818:Animals; D001310:Auranofin / Q000008:administration & dosage / Q000627:therapeutic use*; D015152:Blotting, Northern; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003042:Cocaine / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008111:Liver Function Tests; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
D008565:Membrane Proteins; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D001310:Auranofin; D003577:Cytochrome P-450 Enzyme System; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D003042:Cocaine