ACETAMINOPHEN-INDUCED HEPATOTOXICITY IS ASSOCIATED WITH EARLY CHANGESIN AP-1 DNA-BINDING ACTIVITY

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.