Me. Blazka et al., ACETAMINOPHEN-INDUCED HEPATOTOXICITY IS ASSOCIATED WITH EARLY CHANGESIN AP-1 DNA-BINDING ACTIVITY, Research communications in molecular pathology and pharmacology, 92(3), 1996, pp. 259-273
The AP-1 transcription factor family, which is involved in early respo
nse genes, consists of two groups of proteins, Fos-related antigens (f
ra) and Jun proteins. AP-1 is usually expressed at low basal cellular
levels, but can be up-regulated by a variety of exogenous stimuli whic
h results in synthesis of Fos and Jun proteins and increased AP-1 DNA
binding activity. Changes in early immediate gene responses are associ
ated with liver necrosis, inflammation and repair, although investigat
ions into their role in drug-induced hepatotoxicity have not been acti
vely 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 CR
E 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 d
ifferent 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 A
P-1 activity, remained activated following normalization of liver enzy
me levels. These studies suggest that the AP-1 transcription factor an
d associated genes are associated in the hepatotoxic response of liver
to APAP and may serve as useful molecular biomarkers for chemical-ind
uced hepatotoxicity.