ToxSci Advance Access originally published online on March 31, 2004
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Toxicological Sciences 79, 335-344 (2004)
Toxicological Sciences vol. 79 no. 2 © Society of Toxicology; all rights reserved.
Ochratoxin A Induces Apoptosis in Human Lymphocytes through Down Regulation of Bcl-xL
* INSERM UMR-S 461, Faculté de Pharmacie Paris XI, 5 rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France; and Laboratoire de Toxicologie, Faculté de Pharmacie, Université Saint-Joseph, Beirut, Lebanon
Received December 18, 2003; accepted February 27, 2004
Ochratoxin A (OTA) is a widespread mycotoxin contaminating feed and food. Besides its potent nephrotoxicity, OTA also affects the immune system. We demonstrate here a role for Bcl-xL in OTA-induced apoptosis in human lymphocytes. In particular, human peripheral blood lymphocytes and the human lymphoid T cell line, Kit 225 cells, underwent apoptosis in a time- and dose-dependent manner. This apoptosis was inhibited by z-VAD.fmk, suggesting that caspases were responsible for the induction of apoptosis. Moreover, OTA triggered mitochondrial transmembrane potential (
m) loss and caspase-9 and caspase-3 activation. Interestingly, Bcl-xL protein expression was decreased by OTA treatment, whereas Bcl-2 protein level was not affected. Down-regulation of bcl-xL mRNA was not observed in cells treated with OTA. Overexpression of Bcl-xL in Kit 225 cells protected them against mitochondrial perturbation and retarded the appearance of apoptotic cells. Taken together, our data indicate that mitochondria are a central component in OTA-induced apoptosis and that the loss of Bcl-xL may participate in OTA-induced cell death.
Key Words: ochratoxin A; Bcl-xL; mitochondria; lymphocyte; apoptosis.
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