CHLORPROMAZINE PROTECTION AGAINST CA2+-DEPENDENT AND OXIDATIVE CELL INJURY - LIMITATIONS DUE TO DEPRESSED MITOCHONDRIAL-FUNCTION
CHLORPROMAZINE PROTECTION AGAINST CA2+-DEPENDENT AND OXIDATIVE CELL INJURY - LIMITATIONS DUE TO DEPRESSED MITOCHONDRIAL-FUNCTION
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DOI：
10.1016/0006-2952(94)90577-0
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发表时间：
1994-10-07
影响因子：
5.8
通讯作者：
DOUGHERTY, JM
中科院分区：
文献类型：
--
作者：
BABSON, JR;GAVITT, NE;DOUGHERTY, JM
Chlorpromazine (CPZ), a phenothiazine, demonstrated both cytoprotective and toxic effects on cardiomyocytes. CPZ markedly reduced cytotoxicity caused by two toxic challenges, each with a distinct cytotoxic mechanism. Lethal cell injury was induced in cultured neonatal cardiomyocytes by either: (1) ionomycin, a Ca2+ inophore that caused Ca2+-dependent cell injury; or (2) ethacrynic acid (EA), a glutathione (GSH) depletor that killed cells primarily via peroxidative damage. Pretreatment with 50 mu M CPZ reduced the extent of ionomycin-induced cell death, as measured by lactate dehydrogenase (LDH) leakage, but enhanced the loss of intracellular ATP and collapsed the mitochondrial transmembrane potential (Delta Psi). In EA-treated cultures, 50 mu M CPZ also lowered LDH leakage and diminished the peroxidative damage responsible for the cytotoxicity, but again enhanced the loss of intracellular ATP and collapsed the Delta Psi. CPZ protection was incomplete and limited to a narrow concentration range that was essentially identical for both toxic challenges. Maximum protection was observed with 50 mu M CPZ, yet the amount of residual damage was similar to the degree of injury caused by a mitochondrial uncoupler, carbonylcyanide-m-chlorophenylhydrazone alone. In the absence of either challenge, 50 mu M CPZ did not affect cellular energy status or kill the cells, but a higher concentration of CPZ (150 mu M) did deenergize unchallenged cardiomyocytes. These data demonstrate that CPZ can reduce cytotoxicity caused by either Ca2+-dependent events or oxidative stress. However, even at an optimally protective level, CPZ in combination with either ionomycin or EA deenergized the cells, although neither toxic challenge nor 50 mu M CPZ alone seriously affected Delta Psi. It would appear that intracellular perturbations induced by either challenge promote a depression of mitochondrial function by CPZ, which limits the protective action of the drug. Since both of the challenges used contain toxicologic features exhibited by a wide variety of toxic insults, results of this study have both mechanistic and clinical implications.
