title: Development of PEGylated serum albumin with multiple reduced thiols as a long-circulating scavenger of reactive oxygen species for the treatment of fulminant hepatic failure in mice.
abstract: Reactive oxygen species (ROS) are involved in the pathophysiology of fulminant hepatic failure. Therefore, we developed polyethylene glycol-conjugated bovine serum albumin with multiple reduced thiols (PEG-BSA-SH) for the treatment of fulminant hepatic failure. As a long-circulating ROS scavenger, PEG-BSA-SH effectively scavenged highly reactive oxygen species and hydrogen peroxide in buffer solution. PEG-BSA-SH showed a long circulation time in the plasma after intravenous injection into mice. Fulminant hepatic failure was induced by intraperitoneal injection of lipopolysaccharide and D-galactosamine (LPS/D-GalN) into mice. The LPS/D-GalN-induced elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was significantly inhibited by a bolus intravenous injection of PEG-BSA-SH. Furthermore, the changes in hepatic lipid peroxide and hepatic blood flow were effectively suppressed by PEG-BSA-SH. In contrast, L-cysteine, glutathione, and dithiothreitol, three traditional reduced thiols, had no statistically significant effects on the serum levels of ALT or AST. These findings indicate that PEG-BSA-SH is a promising ROS scavenger and useful in the treatment of fulminant hepatic failure.
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: hkatsumi@mb.kyoto-phu.ac.jp.
authors: Hidemasa
authors: H
authors: Katsumi
authors: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Makiya
authors: M
authors: Nishikawa
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Kazushi
authors: K
authors: Nishiyama
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Rikiya
authors: R
authors: Hirosaki
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Narumi
authors: N
authors: Nagamine
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Haruka
authors: H
authors: Okamoto
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Hironori
authors: H
authors: Mizuguchi
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Kosuke
authors: K
authors: Kusamori
authors: Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Hiroyuki
authors: H
authors: Yasui
authors: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Fumiyoshi
authors: F
authors: Yamashita
authors: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Mitsuru
authors: M
authors: Hashida
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Toshiyasu
authors: T
authors: Sakane
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Akira
authors: A
authors: Yamamoto
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002417:Cattle; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Albumin; Drug delivery; Free radicals; Fulminant hepatic failure; Reactive oxygen species; Reduced thiol; Sepsis