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TOXICOLOGY

Alterations in the Rat Serum Proteome during Liver Injury from Acetaminophen Exposure

Proteomics Group (B.A.M., M.E.B., J.H.M., B.A.W.), Laboratory of Experimental Pathology (J.F.), and Mass Spectrometry Group (K.B.T.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and Large Scale Biology Corporation, Germantown, Maryland (R.P., M.Z., A.J.M., A.M.M., J.X.Z., J.T.)

Changes in the serum proteome were identified during early, fulminant, and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, noninjury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 to 120 h. Two-dimensional gel electrophoresis of immunodepleted serum separated approximately 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum alanine aminotransferase/aspartate aminotransferase levels and histopathology revealed the greatest liver damage at 24 and 48 h after high-dose acetaminophen corresponding to the time of greatest serum protein alterations. After 24 h, 68 serum proteins were significantly altered of which 23 proteins were increased by >5-fold and 20 proteins were newly present compared with controls. Only minimal changes in serum proteins were noted at the low dose without any histopathology. Of the 54 total protein isoforms identified by mass spectrometry, gene ontology processes for 38 unique serum proteins revealed involvement of acute phase response, coagulation, protein degradation, intermediary metabolism, and various carrier proteins. Elevated serum tumor necrosis factor- from 24 to 48 h suggested a mild inflammatory response accompanied by increased antioxidant capability demonstrated by increased serum catalase activity. Antibody array and enzyme-linked immunosorbent assay analyses also showed elevation in the chemokine monocyte chemoattractant protein-1 and the metalloprotease inhibitor tissue inhibitor of metalloproteinases-1 during this same period of liver injury. This study demonstrates that serum proteome alterations probably reflect both liver damage and a concerted, complex response of the body for organ repair and recovery during acute hepatic injury.

Address correspondence to: Dr. B. Alex Merrick, National Institute of Environmental Health Sciences, D2-04, P.O. Box 12233, Research Triangle Park, NC 27709. E-mail: merrick{at}niehs.nih.gov

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