Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kappa B and NF-IL6 DNA binding activity.
Blazka-ME; Germolec-DR; Simeonova-P; Bruccoleri-A; Pennypacker-KR; Luster-MI
J Inflam 1996 Oct; 47(3):138-150
Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and. thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-l transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators aL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.
Hepatotoxins; Analgesics; Genetic-factors; Liver-damage; Liver-disorders; Laboratory-animals; Animal-studies; Enzyme-activity; DNA-damage
Dr. Michael I. Luster, NIOSH, HELD, 1095 Willowdale Rd, Morgantown, WV, 26505
Journal of Inflammation