Protection by cyclosporin A of cultured hepatocytes from the toxic consequences of the loss of mitochondrial energization produced by 1-methyl-4-phenylpyridinium.
Cyclosporin A prevented the killing of cultured rat hepatocytes by 1-methyl-4-phenylpyridinium (MPP+). However, in the presence of both cyclosporin and atractyloside, there was no protection. Cyclosporin had no effect on the depletion of ATP or the loss of mitochondrial energization by MPP+. Cyclosporin, however, did prevent the increase in the molecular order of hepatocyte membranes produced by MPP+. These data suggest that mitochondrial de-energization produced by MPP+ is accompanied by a "permeability transition" analogous to that which occurs in vitro in the presence of calcium. By preventing this transition, cyclosporin protects the cells. By antagonizing this action of cyclosporin, atractyloside restores the cell killing. The mitochondrial transition is causally linked to cell killing by a mechanism that increases the molecular order of the hepatocyte plasma membrane.
Snyder
J W
JW
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
Pastorino
J G
JG
Attie
A M
AM
Farber
J L
JL
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001278:Atractyloside; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D015655:1-Methyl-4-phenylpyridinium