Expression profiling of acetaminophen liver toxicity in mice using microarray technology

Drug-induced hepatotoxicity causes significant morbidity and mortality and is a major concern in drug development, This is due, in large part, to insu fficient knowledge of the mechanism(s) of drug-induced liver injury. In ord er to address this problem, we have evaluated the modulation of gene expres sion within the livers of mice treated with a hepatotoxic dose of acetamino phen (APAP) using high-density oligonucleotide microarrays capable of deter mining the expression profile of >11,000 genes and expressed sequence tags (ESTs), Significant alterations in gene expression, both positive and negat ive, were noted within the livers of APAP-treated mice. APAP-induced toxici ty affected numerous aspects of liver physiology causing, for instance, >tw ofold increased expression of genes that encode for growth arrest and cell cycle regulatory proteins, stress-induced proteins, the transcription facto r LRG-21, suppressor of cytokine signaling (SOCS)-2-protein, and plasminoge n activator inhibitor-1 (PAI-1), A number of these and other genes and ESTs were detectable within the liver only after APAP treatment suggesting thei r potential importance in propagating or preventing further toxicity. These data provide new directions for mechanistic studies that may lead to a bet ter understanding of the molecular basis of drug-induced liver injury and, ultimately, to a more rational design of safer drugs. (C) 2001 Academic Pre ss.