ACETAMINOPHEN-INDUCED HEPATOTOXICITY IS ASSOCIATED WITH EARLY CHANGESIN NF-KAPPA-B AND NF-IL6 DNA-BINDING ACTIVITY

Nuclear transcription factors, such as NF-B and NF-IL6, are believed t o play an important role in regulating the expression of genes that en code for products involved in tissue damage and inflammation and, thus , may represent early biomarkers for chemical toxicities. In the prese nt study changes in DNA binding activity of these factors were examine d in livers of mice administered hepatotoxic doses of acetaminophen (A PAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatoto xic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs un der similar conditions. These changes corresponded with increased rele ase of inflammatory mediators (IL-6, serum amyloid A) and increased le vels of enzymatic markers of hepatocyte damage. Similarly, treatment o f mice with gadolinium chloride, an inhibitor of Kupffer cell activati on and known to protect against APAP-induced hepatotoxicity, reduced t he observed pathophysiological response in the liver while altering th e APAP-associated changes in NF-kB DNA binding activity. NF-kB was fou nd predominantly in parenchymal and endothelial cells mad was composed primarily of relatively inactive p50 homodimer subunits in control li ver. Taken together, these studies suggest that hepatotoxicity is asso ciated with early and complex changes in DNA binding activities of spe cific transcription factors. fn particular NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators an d is analogous to that previously observed in certain other cell syste ms such as B lymphocytes. (C) 1997 Wiley-Liss, Inc.