TY - JOUR
T1 - Acetaminophen-induced hepatotoxicity is associated with early changes in AP-1 DNA binding activity
AU - Blazka, Mark E.
AU - Bruccoleri, Alessandra
AU - Simenova, Petia P.
AU - Germolec, Dori R.
AU - Pennypacker, Keith R.
AU - Luster, Michael I.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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.
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M3 - Article
C2 - 8827825
AN - SCOPUS:0029957016
SN - 1078-0297
VL - 92
SP - 259
EP - 273
JO - Research Communications in Molecular Pathology and Pharmacology
JF - Research Communications in Molecular Pathology and Pharmacology
IS - 3
ER -