State Key Laboratories of Natural and Biomimetic Drugs, Peking University, Beijing 100083, PR China.
J Inorg Biochem. 2010 Apr;104(4):371-8. doi: 10.1016/j.jinorgbio.2009.11.007. Epub 2009 Nov 27.
Vanadium compounds have been regarded as promising in therapeutic treatment of diabetes and in cancer prevention. In the present work, we studied the effects of vanadium compounds on mitochondria to investigate the mechanisms of toxicity. Mitochondria were isolated from rat liver and incubated with a variety of vanadium compounds, i.e. VOSO(4), NaVO(3), and vanadyl complexes with organic ligands. Our studies indicated that VO(2+), VO(3)(-), VO(acac)(2) and VOcit (1-100microM) could induce mitochondrial swelling in a concentration dependent manner and disrupt mitochondrial membrane potential (Deltapsi(m)) in a time dependent manner, which is quite different from the rapid Deltapsi(m) collapse caused by Ca(2+) or CCCP (carbonyl cyanide m-chlorophenylhydrazone, a mitochondrial uncoupling reagent). Release of cytochrome c (Cyt c) was observed and could be inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore (PTP). Interestingly, VOdipic caused release of Cyt c without mitochondrial swelling and Deltapsi(m) disruption, an action previously only observed on the Bax protein, suggesting a potentially role of VOdipic in regulating PTP opening. In addition, all the vanadium compounds tested stimulated mitochondrial production of reactive oxygen species (ROS). Antioxidants, i.e. vitamin C and E, significantly delayed the Deltapsi(m) disruption. Overall, our experimental evidence indicated vanadium compounds exhibited multiple actions on mitochondria. Vanadium compounds did induce oxidative stress on mitochondrial and thus caused PTP opening, which led to collapse of Deltapsi(m) and Cyt c release as the initiation of cell apoptosis.
钒化合物已被认为在糖尿病的治疗和癌症预防方面具有广阔的应用前景。本研究探讨了钒化合物对线粒体的作用，旨在研究其毒性作用机制。采用差速离心法从大鼠肝组织中分离线粒体，与多种钒化合物（硫酸氧钒、偏钒酸钠、有机配位钒氧配合物）孵育。结果表明，VO2+、VO3-、VO(acac)2和 VOcit（1-100μM）可浓度依赖性诱导线粒体肿胀，并呈时间依赖性破坏线粒体膜电位（Deltapsi(m)），这与 Ca2+或 CCCP（羰基氰化物 m-氯代苯腙，一种线粒体解偶联剂）引起的快速 Deltapsi(m)崩溃明显不同。实验观察到细胞色素 c（Cyt c）释放，且这种释放可被线粒体通透性转换孔（PTP）抑制剂环孢菌素 A（CsA）所抑制。有趣的是，VOdipic 引起 Cyt c 释放而不伴有线粒体肿胀和 Deltapsi(m)破坏，这种作用以前仅在 Bax 蛋白中观察到，提示 VOdipic 可能在调节 PTP 开放方面具有潜在作用。此外，所有测试的钒化合物均可刺激线粒体产生活性氧（ROS）。抗氧化剂（如维生素 C 和 E）可显著延迟 Deltapsi(m)破坏。综上，本实验证据表明钒化合物对线粒体具有多种作用。钒化合物可诱导线粒体氧化应激，从而导致 PTP 开放，引起 Deltapsi(m)崩溃和 Cyt c 释放，这可能是细胞凋亡的起始步骤。
