Related Experiment Video
Updated: Aug 13, 2026
Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue
Published on: March 23, 2015
Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-) mice
Michie M K Ong1, Audrey S Wang, Koon Yeow Leow
1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Abstract:
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.
Insights
Nimesulide exacerbates liver injury in mice with genetic mitochondrial defects. This drug potentiates oxidative stress and triggers apoptosis, highlighting a risk in individuals with compromised mitochondrial function.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Toxicology
Background:
- Nimesulide, a COX-2 inhibitor, is linked to rare liver damage.
- Oxidative stress and mitochondrial dysfunction are implicated in nimesulide-induced hepatotoxicity.
- The precise mechanisms underlying this liver injury remain unclear.
Purpose of the Study:
- To investigate if genetic mitochondrial abnormalities sensitize mice to nimesulide's hepatotoxicity.
- To explore the role of impaired mitochondrial function and oxidative stress in nimesulide's adverse effects.
Main Methods:
- Utilized heterozygous superoxide dismutase 2 (Sod2(+/-)) mice, exhibiting silent mitochondrial stress.
- Administered nimesulide (10 mg/kg, ip, bid) for 4 weeks, a human-equivalent dose.
- Assessed hepatic mitochondrial oxidative injury markers, apoptosis, and in vitro mitochondrial superoxide production.
Main Results:
- Nimesulide potentiated mitochondrial oxidative injury (decreased aconitase activity, increased protein carbonyls) specifically in Sod2(+/-) mice.
- Nimesulide-treated Sod2(+/-) mice showed increased cytochrome c and caspase-3 activity, indicating apoptosis.
- In vitro studies revealed nimesulide increased mitochondrial superoxide anion in Sod2(+/-) mice.
Conclusions:
- Repeated nimesulide administration exacerbates oxidant stress and mitochondrial damage in genetically compromised mice.
- Nimesulide activates pro-apoptotic factors in the context of impaired mitochondrial function.
- This study suggests a potential risk of nimesulide-induced liver injury in individuals with underlying mitochondrial dysfunction.
