Hexavalent chromium targets mitochondrial respiratory chain complex             I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes.
Hexavalent chromium [Cr(VI)], which is used for various industrial applications,             such as leather tanning and chroming, can cause a number of human diseases including             inflammation and cancer. Cr(VI) exposure leads to severe damage to the liver,             but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear.             The present study provides evidence that Cr(VI) enhances reactive oxygen species             (ROS) accumulation by inhibiting the mitochondrial respiratory chain complex (MRCC)             I. Cr(VI) did not affect the expression levels of antioxidative proteins such             as superoxide dismutase (SOD), catalase and thioredoxin (Trx), indicating that             the antioxidative system was not involved in Cr(VI)-induced ROS accumulation.             We found that ROS mediated caspase-3 activation partially depends on the downregulation             of the heat shock protein (HSP) 70 and 90. In order to confirm our hypothesis             that ROS plays a key role in Cr(VI)-mediated cytotoxicity, we used N-acetylcysteine             (NAC) to inhibit the accumulation of ROS. NAC successfully blocked the inhibition             of HSP70 and HSP90 as well as the activation of caspase-3, suggesting that ROS             is essential in Cr(VI)-induced caspase-3 activation. By applying different MRCC             substrates as electron donors, we also confirmed that Cr(VI) could accept the             electrons leaked from MRCC I and the reduction occurs at MRCC I. In conclusion,             the present study demonstrates that Cr(VI) induces ROS-dependent caspase-3 activation             by inhibiting MRCC I activity, and MRCC I has been identified as a new target             and a new mechanism for the apoptosis-inducing activity displayed by Cr(VI).
Department of Health Toxicology, School of Public Health, Central                     South University, Changsha 410078, P.R. China.
Fang
F
Xiao
Yanhong
Y
Li
Lu
L
Dai
Yuanyuan
Y
Deng
Yue
Y
Zou
Peng
P
Li
Yuan
Y
Yang
Caigao
C
Zhong
D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D002857:Chromium; C074702:chromium hexavalent ion; D053148:Caspase 3; D042967:Electron Transport Complex I