Mitochondrial uncoupling by the sulindac metabolite, sulindac sulfide.
Sulindac is a non-steroidal antiinflammatory drug (NSAID) known to inhibit cyclooxygenases (COX) 1 and 2, and at present of interest for cancer prevention. However, its therapeutic use has been limited by its toxicity to the gastrointestinal tract and liver. We address the effects of sulindac, of the pharmacologically inactive metabolite, sulindac sulfone, and of the pharmacologically active metabolite, sudindac sulfide, on isolated rat liver mitochondria and HepG2 cells. Sulindac sulfide, but not sulindac sulfone or sulindac itself, caused mitochondrial uncoupling, released preaccumulated Ca2+ from the organelle, and decreased Hep-G2 cell viability in apparent association with cell ATP depletion resulting from mitochondrial uncoupling-associated membrane potential dissipation.
Leite
Samara
S
Department of Clinical Analysis, Toxicology, Bromatology, Faculty of Pharmaceutical Sciences, Ribeirao Preto-USP, Sao Paulo, Brazil.
Martins
Nádia Maria
NM
Dorta
Daniel Junqueira
DJ
Curti
Carlos
C
Uyemura
Sérgio Akira
SA
dos Santos
Antonio Cardozo
AC
D000818:Animals; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
D014475:Uncoupling Agents; D013467:Sulindac; C025462:sulindac sulfide