A protective role for cyclooxygenase-2 in drug-induced liver injury in mice.
Despite the utility of cyclooxygenase (COX) inhibition as an antiinflammatory strategy, prostaglandin (PG) products of COX-1 and -2 provide important regulatory functions in some pathophysiological states. Scattered reports suggest that COX inhibition may also promote adverse drug events. Here we demonstrate a protective role for endogenous COX-derived products in a murine model of acetaminophen (APAP)-induced acute liver injury. A single hepatotoxic dose caused the selective induction of COX-2 mRNA and increased PGD2 and PGE2 levels within the livers of COX(+/+) male mice suggesting a role for COX-2 in this model of liver injury. APAP-induced hepatotoxicity and lethality were markedly greater in COX-2(-/-) and (-/+) mice in which normal PG responsiveness is altered. The significantly increased toxicity linked to 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 surrogate for bioactivation and toxicity. Microarray analyses indicated that increased injury associated with COX-2 deficiency coincided, most notably, with a profoundly impaired induction of heat shock proteins in COX-2(-/+) mice suggesting that PGs may act as critical endogenous stress signals following drug insult. These findings suggest that COX-2-derived mediators serve an important hepato-protective function and that COX inhibition may contribute to the risk of drug-induced liver injury, possibly through both nonimmunological and immunological pathways.
Reilly
T P
TP
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, NHLBI, NIH, 9000 Rockville Pike, Building 10, Room 8N110, Bethesda, Maryland 20892-1760, USA. ReillyT@nhlbi.nih.gov
Brady
J N
JN
Marchick
M R
MR
Bourdi
M
M
George
J W
JW
Radonovich
M F
MF
Pise-Masison
C A
CA
Pohl
L R
LR
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000068579:Celecoxib; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015151:Immunoblotting; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011720:Pyrazoles; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D015996:Survival Rate
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D000082:Acetaminophen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone; D015230:Prostaglandin D2