Tributyltin interacts with mitochondria and induces cytochrome c release.
Although triorganotins are potent inducers of apoptosis in various cell types, the critical targets of these compounds and the mechanisms by which they lead to cell death remain to be elucidated. There are two major pathways by which apoptotic cell death occurs: one is triggered by a cytokine mediator and the other is by a mitochondrion-dependent mechanism. To elucidate the mechanism of triorganotin-induced apoptosis, we studied the effect of tributyltin on mitochondrial function. We found that moderately low doses of tributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. Tributyltin-induced cytochrome c release is also prevented by dithiols such as dithiothreitol and 2,3-dimercaptopropanol but not by monothiols such as GSH, N-acetyl-L-cysteine, L-cysteine and 2-mercaptoethanol. Further studies with phenylarsine oxide agarose revealed that tributyltin interacts with the adenine nucleotide translocator, a functional constituent of the mitochondrial permeability transition pore, which is selectively inhibited by dithiothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translocator and opens the permeability transition pore, thereby decreasing membrane potential and releasing cytochrome c from mitochondria, a series of events consistent with established mechanistic models of apoptosis.
Nishikimi
A
A
Department of Biochemistry and Molecular Pathology, Osaka City University Medical School, Osaka 545-8585, Japan.
Kira
Y
Y
Kasahara
E
E
Sato
E F
EF
Kanno
T
T
Utsumi
K
K
Inoue
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000633:toxicity*
D003574:Cytochrome c Group; D009840:Oligomycins; D013438:Sulfhydryl Compounds; D014220:Trialkyltin Compounds; C011559:tributyltin; D004533:Egtazic Acid; D000226:Mitochondrial ADP, ATP Translocases