Acetaminophen-induced hepatotoxicity is associated with early changes in AP-1 DNA binding activity

Mark E. Blazka, Alessandra Bruccoleri, Petia P. Simenova, Dori R. Germolec, Keith R. Pennypacker, Michael I. Luster

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The AP-1 transcription factor family, which is involved in early response genes, consists of two groups of proteins, Fos-related antigens (fra) and Jun proteins AP-1 is usually expressed at low basal cellular levels, but can be up-regulated by a variety of exogenous stimuli which results in synthesis of Fos and Jun proteins and increased AP-1 DNA binding activity. Changes in early immediate gene responses are associated with liver necrosis, inflammation and repair, although investigations into their role in drug-induced hepatotoxicity have not been actively examined. In the present studies, we determined that exposure to necrogenic doses of acetaminophen (APAP) was associated with increased AP-1 DNA binding activity in mouse liver. The APAP-induced hepatic AP-1 DNA binding complex had affinity for both the consensus AP-1 and CRE sequences. Furthermore, c-jun, but not c- fos, mRNA transcripts were transiently increased following exposure to hepatotoxic doses of APAP. When endotoxin was administered to mice in order to elicit a hepatic inflammatory response without necrosis, increases in c- jun expression occurred without accompanying changes in AP-1 activity, indicating a different mechanism of action. When compared to conventional indicators of hepatotoxicity, such as plasma levels of liver-associated enzymes, changes in gene expression occurred much earlier and, at least with AP-1 activity, remained activated following normalization of liver enzyme levels. These studies suggest that the AP-1 transcription factor and associated genes are associated in the hepatotoxic response of liver to APAP and may serve as useful molecular biomarkers for chemical-induced hepatotoxicity.

Original languageEnglish
Pages (from-to)259-273
Number of pages15
JournalResearch Communications in Molecular Pathology and Pharmacology
Volume92
Issue number3
StatePublished - 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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