title: Farnesyltransferase inhibitor, tipifarnib, prevents galactosamine/lipopolysaccharide-induced acute liver failure.
abstract: Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. There is no cure for ALF except liver transplantation. Protein farnesylation is a lipid modification of cysteine residues that is catalyzed by farnesyltransferase (FTase) and has been proposed as an integral component of acute inflammation. Previously, we have demonstrated that FTase inhibitors improve survival in mouse models of endotoxemia and sepsis. Here we studied the effects of FTase inhibitor, tipifarnib, on galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF. The effects of tipifarnib (10 mg/kg, i.p.) were studied in GalN (400 mg/kg, i.p.)- and LPS (3 μg/kg)-challenged mice by histological and biochemical analyses. Galactosamine/LPS administration caused prominent liver injury characterized by the increased plasma alanine aminotransferase and aspartic aminotransferase levels, leading to significant mortality in mice. Tipifarnib inhibited GalN/LPS-induced caspase 3 activation, inflammatory cytokine production, and c-Jun N-terminal kinase phosphorylation in the liver. On the other hand, tipifarnib upregulated antiapoptotic protein, Bcl-xL, in the liver after GalN/LPS challenge. Tipifarnib also protected primary hepatocytes from GalN/tumor necrosis factor α-induced cell death by inhibiting caspase 3 activation and upregulating antiapoptotic proteins. Galactosamine/LPS-induced liver injury was associated with increased protein farnesylation in the liver. Tipifarnib prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in GalN/LPS-challenged mice. These results suggest that protein farnesylation is a novel potential molecular target to prevent hepatocyte death and acute inflammatory liver failure in fulminant hepatitis.
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shirozu
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Shriners Hospitals for Children, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Shriners Hospitals for Children, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hisaka
authors.affiliation: Shriners Hospitals for Children, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005688:Galactosamine / Q000737:chemistry*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008070:Lipopolysaccharides / Q000737:chemistry*; D008099:Liver / Q000201:enzymology / Q000293:injuries / Q000378:metabolism; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015363:Quinolones / Q000737:chemistry*; D018805:Sepsis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008055:Lipids; D008070:Lipopolysaccharides; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D051231:Farnesyltranstransferase; D053148:Caspase 3; C402769:tipifarnib