Y-40138, a multiple cytokine production modulator, protects against D-galactosamine and lipopolysaccharide-induced hepatitis.
Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs are associated with tumor necrosis factor (TNF) production. D-Galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure. In this model, TNF-alpha plays a central role in the pathogenesis of D-GalN/LPS-induced liver injury in mice. Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl inhibits TNF-alpha and augments interleukin (IL)-10 production in LPS-injected mice in plasma. In the present study, we examined the effect of Y-40138 on D-GalN/LPS-induced hepatitis. Y-40138 (10mg/kg, i.v.) significantly suppressed TNF-alpha and monocyte chemoattractant protein-1 (MCP-1) production and augmented IL-10 production in plasma. In addition, Y-40138 significantly inhibited TNF-alpha production induced by direct interaction between human T lymphocytes and macrophages. Y-40138 suppressed plasma alanine transaminase (ALT) elevation and improved survival rate in D-GalN/LPS-injected mice, and it is suggested that the protective effect of Y-40138 on hepatitis may be mediated by inhibition of TNF-alpha and MCP-1, and/or augmentation of IL-10. This compound is expected to be a new candidate for treatment of cytokine and/or chemokine-related liver diseases such as alcoholic hepatitis.
Fukuda
Tetsuko
T
Marketing and Planning Department, Sales and Marketing Division, Mitsubishi Pharma Corporation, 2-5-6 Awaji-machi, Chuo-ku, Osaka 541-0047, Japan. Fukada.Tetsuko@mf.m-pharma.co.jp
Mogami
Akira
A
Tanaka
Hideki
H
Yoshikawa
Tsutomu
T
Hisadome
Masao
M
Komatsu
Hirotsugu
H
D000081:Acetamides / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D005688:Galactosamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D022781:Hepatocytes / Q000473:pathology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000081:Acetamides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; D005688:Galactosamine; D000410:Alanine Transaminase