Acetaminophen-induced hepatotoxicity is associated with early changes in AP-1 DNA binding activity.
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.
Blazka
M E
ME
Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Bruccoleri
A
A
Simeonova
P P
PP
Germolec
D R
DR
Pennypacker
K R
KR
Luster
M I
MI
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011485:Protein Binding; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D018808:Transcription Factor AP-1; D000082:Acetaminophen; D004247:DNA