Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-) mice.
Nimesulide, a preferential COX-2 inhibitor, has been associated with rare idiosyncratic hepatotoxicity. The underlying mechanisms of liver injury are unknown, but experimental evidence has identified oxidative stress as a potential hazard and mitochondria as a target. The aim of this study was to explore whether genetic mitochondrial abnormalities, resulting in impaired mitochondrial function and mildly increased oxidative stress, might sensitize mice to the hepatic adverse effects of nimesulide. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model, as these mice develop clinically silent mitochondrial stress but otherwise appear normal. Nimesulide was administered for 4 weeks (10 mg/kg, ip, bid), at a dose equivalent to human therapeutic dosage. We found that the drug potentiated hepatic mitochondrial oxidative injury (decreased aconitase activity, increased protein carbonyls) in Sod2(+/-), but not wild-type, mice. Furthermore, the nimesulide-treated mutant mice exhibited increased hepatic cytosolic levels of cytochrome c and caspase-3 activity, as well as increased numbers of apoptotic hepatocytes. Finally, nimesulide in vitro caused a concentration-dependent net increase in superoxide anion in mitochondria from Sod2(+/-), but not Sod2(+/+) mice. In conclusion, repeated administration of nimesulide can superimpose an oxidant stress, potentiate mitochondrial damage, and activate proapoptotic factors in mice with genetically compromised mitochondrial function.
Ong
Michie M K
MM
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Wang
Audrey S
AS
Leow
Koon Yeow
KY
Khoo
Yok Moi
YM
Boelsterli
Urs A
UA
D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006579:Heterozygote; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000154:Aconitate Hydratase; D000255:Adenosine Triphosphate; D020169:Caspases; D045304:Cytochromes c; D005978:Glutathione; D013449:Sulfonamides; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C012655:nimesulide