The hepatotoxicity of cadmium-based quantum dots (Cd-QDs) has become the focus with their extensive applications in biomedicine. Previous reports have demonstrated that high oxidative stress and consequent redox imbalance play critical roles in their toxicity mechanisms. Intracellular antioxidant proteins, such as thioredoxin 1 (Trx1) and peroxiredoxin 1 (Prx1), could regulate redox homeostasis through thiol-disulfide exchange. Herein, we hypothesized that the excessive reactive oxygen species (ROS) induced by Cd-QD exposure affects the functions of Trx1 or Prx1, which further causes abnormal apoptosis of liver cells and hepatotoxicity. Thereby, three types of Cd-QDs, CdS, CdSe, and CdTe QDs, were selected for conducting an intensive study. Under the same conditions, the H2O2 level in the CdTe QD group was much higher than that of CdS or CdSe QDs, and it also corresponded to the higher hepatotoxicity. Mass spectrometry (MS) results show that excessive H2O2 leads to sulfonation modification (−SO3H) at the active sites of Trx1 (Cys32 and Cys35) and Prx1 (Cys52 and Cys173). The irreversible oxidative modifications broke their cross-linking with the apoptosis signal-regulating kinase 1 (ASK1), resulting in the release and activation of ASK1, and activation of the downstream JNK/p38 signaling finally promoted liver cell apoptosis. These results highlight the key effect of the high oxidative stress, which caused irreversible oxidative modifications of Trx1 and Prx1 in the mechanisms involved in Cd-QD-induced hepatotoxicity. This work provides a new perspective on the hepatotoxicity mechanisms of Cd-QDs and helps design safe and reliable Cd-containing nanoplatforms.
镉基量子点(Cd-QDs)的肝毒性已成为其在
生物医学中广泛应用的关注焦点。先前的报告表明,高
氧化应激和随之而来的
氧化还原失衡在其毒性机制中起着关键作用。细胞内抗
氧化蛋白,如
硫氧还蛋白1(Trx1)和过
氧化物还原酶1(Prx1),可通过
硫醇-二
硫键交换来调节
氧化还原平衡。在此,我们假设Cd-QD暴露引起的过量活性
氧(R
OS)会影响Trx1或Prx1的功能,进而导致肝细胞异常凋亡和肝毒性。因此,我们选择三种类型的Cd-QDs,即CdS、CdSe和CdTe QDs,进行深入研究。在相同的条件下,CdTe QD组的
H2O2水平远高于CdS或CdSe QDs,这也与较高的肝毒性相对应。质谱(MS)结果表明,过量的 导致Trx1(Cys32和Cys35)和Prx1(Cys52和Cys173)活性位点的磺化修饰(-SO3H)。不可逆的
氧化修饰破坏了它们与凋亡信号调节激酶1(ASK1)的交联,导致ASK1的释放和激活,并激活下游JNK/p38信号传导,最终促进肝细胞凋亡。这些结果强调了高
氧化应激的关键作用