A Protective Role for Cyclooxygenase-2 in Drug-Induced Liver Injury in Mice

详细信息    查看全文

• 作者：Timothy P. Reilly ; John N. Brady ; Michael R. Marchick ; Mohammed Bourdi ; John W. George ; Michael F. Radonovich ; Cynthia A. Pise-Masison ; and Lance R. Pohl
• 刊名：Chemical Research in Toxicology
• 出版年：2001
• 出版时间：December 2001
• 年：2001
• 卷：14
• 期：12
• 页码：1620 - 1628
• 全文大小：998K
• 年卷期：v.14,no.12(December 2001)
• ISSN：1520-5010

文摘

Despite the utility of cyclooxygenase (COX) inhibition as an antiinflammatory strategy,prostaglandin (PG) products of COX-1 and -2 provide important regulatory functions in somepathophysiological states. Scattered reports suggest that COX inhibition may also promoteadverse drug events. Here we demonstrate a protective role for endogenous COX-derivedproducts in a murine model of acetaminophen (APAP)-induced acute liver injury. A singlehepatotoxic dose caused the selective induction of COX-2 mRNA and increased PGD2 and PGE2levels within the livers of COX^+/+ male mice suggesting a role for COX-2 in this model of liverinjury. APAP-induced hepatotoxicity and lethality were markedly greater in COX-2^-/- and ^-/+mice in which normal PG responsiveness is altered. The significantly increased toxicity linkedto COX-2 deficiency could be mimicked using the selective COX-2 inhibitory drug, celecoxib,in COX^+/+ mice and was not due to alterations in drug-protein adduct formation, a surrogatefor bioactivation and toxicity. Microarray analyses indicated that increased injury associatedwith COX-2 deficiency coincided, most notably, with a profoundly impaired induction of heatshock proteins in COX-2^-/+ mice suggesting that PGs may act as critical endogenous stresssignals following drug insult. These findings suggest that COX-2-derived mediators serve animportant hepato-protective function and that COX inhibition may contribute to the risk ofdrug-induced liver injury, possibly through both nonimmunological and immunologicalpathways.