title: Albumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis.
abstract: Overdoses of acetaminophen (APAP) are a major cause of acute liver failure. N-Acetylcysteine (NAC) is the standard therapy for patients with such an overdose because oxidative stress plays an important role in the pathogenesis of APAP-induced hepatitis. However, NAC is not sufficiently efficacious. We previously developed a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx), designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an endogenous protein with antioxidative and anti-inflammatory properties. In this study, we investigated the therapeutic impact of HSA-Trx in mice with APAP-induced hepatitis. The systemic administration of HSA-Trx significantly improved the survival rate of mice treated with a lethal dose of APAP compared with saline. HSA-Trx strongly attenuated plasma transaminases in APAP-induced hepatitis mice compared with HSA or Trx, components of the fusion protein. HSA-Trx also markedly caused a diminution in the histopathological features of hepatic injuries and the number of apoptosis-positive hepatic cells. In addition, an evaluation of oxidative stress markers and plasma cytokine and chemokine levels clearly showed that HSA-Trx significantly improved the breakdown of hepatic redox conditions and inflammation caused by the APAP treatment. HSA-Trx also significantly decreased oxidative and nitrosative/nitrative stress induced by SIN-1 in vitro. Finally, HSA-Trx, but not the NAC treatment at 4 h after APAP injection, significantly inhibited the elevation in plasma transaminase levels. In conclusion, the findings suggest that HSA-Trx has considerable potential for use as a novel therapeutic agent for APAP-induced hepatitis, due to its long-lasting antioxidative and anti-inflammatory effects.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and ‡Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University , 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Maeda
authors.forename: Azusa
authors.initials: A
authors.lastname: Kodama
authors.forename: Saori
authors.initials: S
authors.lastname: Nagao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Victor Tuan Giam
authors.initials: VT
authors.lastname: Chuang
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012709:Serum Albumin / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016207:Cytokines; D012709:Serum Albumin; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase