This Article Free Full Text (Free PDF) Free References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Blazka, M. E. Articles by Luster, M. I. Search for Related Content PubMed PubMed Citation Articles by Blazka, M. E. Articles by Luster, M. I. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETAMINOPHEN Medline Plus Health Information Pain Relievers Social Bookmarking                         What's this?

Histopathology of Acetaminophen-Induced Liver Changes: Role of Interleukin 1 and Tumor Necrosis Factor

Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

Michael R. Elwell

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

Steve D. Holladay

Department of Biomedical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia 24061-0442

Ralph E. Wilson

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

Michael I. Luster

Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

Administration of 500 mg/kg acetaminophen (APAP) to female B6C3F1 mice resulted in well-documented pathophysiological changes in the liver manifested as increased serum concentration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and serum sorbitol dehydrogenase), centrilobular congestion, and hepatocellular degeneration and necrosis. The role of proinflammatory cytokines, including tumor necrosis factor a (TNF-) and interleukin 1 (IL-1), on the hepatotoxicity of APAP was examined at 4,8, 12, and 24 hr following APAP administration. Neutralization of TNF- or IL-1 with specific antibodies partially prevented the hepatotoxic effects of APAP at the 4- and 8-hr time points. In addition, prior administration of anti-TNF- antibodies shortened the recovery time following APAP treatment. While IL-1 receptor antagonist (IL-1ra) had only a modest protective effect against APAP-induced liver damage, as determined by serum enzyme release, IL-1ra had no effect on the degree of hepatic congestion or necrosis at any of the time points examined. On the other hand, administration of antibodies against IL-1ra exacerbated APAP-induced liver toxicity. These results suggest that TNF- and IL-1 play an important role in the degree of damage and recovery that the liver undergoes following APAP intoxication.

Key Words: Female B6C3F1 mice • antibody • proinflammatory • hepatotoxic • centrilobular congestion

Toxicologic Pathology, Vol. 24, No. 2, 181-189 (1996)
DOI: 10.1177/019262339602400206


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. C Henderson, K. J Pollock, J. Frew, A. C Mackinnon, R. A Flavell, R. J Davis, T. Sethi, and K. J Simpson Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure Gut, July 1, 2007; 56(7): 982 - 990. [Abstract] [Full Text] [PDF]

				L. P. James, P. M. Simpson, H. C. Farrar, G. L. Kearns, G. S. Wasserman, J. L. Blumer, M. D. Reed, J. E. Sullivan, J. A. Hinson, and The Pediatric Pharmacology Research Unit Network Cytokines and Toxicity in Acetaminophen Overdose J. Clin. Pharmacol., October 1, 2005; 45(10): 1165 - 1171. [Abstract] [Full Text] [PDF]

				G. E. N. Kass Response: Comments on "Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells" J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1403 - 1404. [Full Text] [PDF]

				P. Macanas-Pirard, N.-S. Yaacob, P. C. Lee, J. C. Holder, R. H. Hinton, and G. E. N. Kass Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 780 - 789. [Abstract] [Full Text] [PDF]

				K. Pande, S. M. Moran, and C. A. Bradfield Aspects of Dioxin Toxicity Are Mediated by Interleukin 1-Like Cytokines Mol. Pharmacol., May 1, 2005; 67(5): 1393 - 1398. [Abstract] [Full Text] [PDF]

				N. Veal, C.-L. Hsieh, S. Xiong, J. M. Mato, S. Lu, and H. Tsukamoto Inhibition of lipopolysaccharide-stimulated TNF-{alpha} promoter activity by S-adenosylmethionine and 5'-methylthioadenosine Am J Physiol Gastrointest Liver Physiol, August 1, 2004; 287(2): G352 - G362. [Abstract] [Full Text] [PDF]

				Y. Ishida, T. Kondo, K. Tsuneyama, P. Lu, T. Takayasu, and N. Mukaida The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice J. Leukoc. Biol., January 1, 2004; 75(1): 59 - 67. [Abstract] [Full Text] [PDF]

				L. P. James, P. R. Mayeux, and J. A. Hinson ACETAMINOPHEN-INDUCED HEPATOTOXICITY Drug Metab. Dispos., December 1, 2003; 31(12): 1499 - 1506. [Abstract] [Full Text] [PDF]

				H. Chiu, C. R. Gardner, D. M. Dambach, J. A. Brittingham, S. K. Durham, J. D. Laskin, and D. L. Laskin Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G959 - G966. [Abstract] [Full Text] [PDF]

				L. P. James, S. S. McCullough, L. W. Lamps, and J. A. Hinson Effect of N-Acetylcysteine on Acetaminophen Toxicity in Mice: Relationship to Reactive Nitrogen and Cytokine Formation Toxicol. Sci., October 1, 2003; 75(2): 458 - 467. [Abstract] [Full Text] [PDF]

				Y. ISHIDA, T. KONDO, T. OHSHIMA, H. FUJIWARA, Y. IWAKURA, and N. MUKAIDA A pivotal involvement of IFN-{gamma} in the pathogenesis of acetaminophen-induced acute liver injury FASEB J, August 1, 2002; 16(10): 1227 - 1236. [Abstract] [Full Text] [PDF]

				C. Caulin, C. F. Ware, T. M. Magin, and R. G. Oshima Keratin-Dependent, Epithelial Resistance to Tumor Necrosis Factor-Induced Apoptosis J. Cell Biol., April 3, 2000; 149(1): 17 - 22. [Abstract] [Full Text] [PDF]

				C. M. Hogaboam, C. L. Bone-Larson, M. L. Steinhauser, A. Matsukawa, J. Gosling, L. Boring, I. F. Charo, K. J. Simpson, N. W. Lukacs, and S. L. Kunkel Exaggerated Hepatic Injury Due to Acetaminophen Challenge in Mice Lacking C-C Chemokine Receptor 2 Am. J. Pathol., April 1, 2000; 156(4): 1245 - 1252. [Abstract] [Full Text] [PDF]

				G. L. Kearns, J. S. Leeder, and G. S. Wasserman Acetaminophen Intoxication During Treatment: What You Don't Know Can Hurt You Clinical Pediatrics, March 1, 2000; 39(3): 133 - 144. [Abstract] [PDF]

				T. L. Horn, T. D. O'Brien, L. B. Schook, and M. S. Rutherford Acute Hepatotoxicant Exposure Induces TNFR-Mediated Hepatic Injury and Cytokine/Apoptotic Gene Expression Toxicol. Sci., March 1, 2000; 54(1): 262 - 273. [Abstract] [Full Text] [PDF]

				A Akbay, K Cinar, O Uzunalimoglu, S Eranil, C Yurdaydin, H Bozkaya, and M Bozdayi Serum cytotoxin and oxidant stress markers in N-acetylcysteine treated thioacetamide hepatotoxicity of rats Human and Experimental Toxicology, November 1, 1999; 18(11): 669 - 676. [Abstract] [PDF]

				R. K. Chawla, W. H. Watson, C. E. Eastin, E. Y. Lee, J. Schmidt, and C. J. McClain S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury Am J Physiol Gastrointest Liver Physiol, July 1, 1998; 275(1): G125 - G129. [Abstract] [Full Text] [PDF]

				T.A. Bertram Role of Toxicologic Pathology in Advancing Understanding of Previously Identified Hazards, Current Safety Assessments, and Mechanism of Action for Therapeutic Xenobiotics Toxicol Pathol, March 1, 1996; 24(2): 151 - 152. [PDF]