Chronic effects of celecoxib, a cyclooxygenase-2 inhibitor, cause enhanced alcohol-induced liver steatosis in rats.
BACKGROUND
The pathogenetic role of prostaglandins in steatosis, the first stage of alcoholic liver injury, is not well understood, especially that involving the inflammatory reactions controlled by prostaglandins and pro-inflammatory cytokines in the liver. We, therefore, studied the chronic effects of the COX-2 inhibitor, celecoxib, given to ethanol-treated rats.


METHODS
Rats were fed ethanol and a low dose of celecoxib (approximately 20 mg/kg daily) in a high-fat/low-carbohydrate liquid diet for six weeks.


RESULTS
Ethanol treatment caused liver steatosis, moderate cellular infiltration and enhanced levels of plasma alanine transaminase (ALT) and tumour necrosis factor-alpha (TNF-alpha). Co-administration of celecoxib further increased the steatosis, relative liver weights and increased plasma ALT and TNF-alpha levels above those in ethanol-treated rats. Also, celecoxib counteracted the ethanol-induced increase in hepatic prostaglandin E(2) receptor EP4 mRNA expression. In contrast, celecoxib alone increased plasma ALT and TNF-alpha levels.


CONCLUSIONS
These results suggest that prolonged low-dose celecoxib treatment with ethanol enhances alcohol-induced steatosis and liver inflammatory reactions above that from ethanol or celecoxib alone. It is suggested that reduction in PGE(2) by treatment with celecoxib removes the endogenous protective effect of this prostaglandin.
Bykov
I L
IL
Department of Mental Health and Alcohol Research, Alcohol Research Center, National Public Health Institute, POB 33, 00251 Helsinki, Finland.
Palmen
M
M
Rainsford
K D
KD
Lindros
K O
KO
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D011720:Pyrazoles / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000009:adverse effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000410:Alanine Transaminase; D000068579:Celecoxib