Brown P C, Sokolove P M, McCann D J, Stevens J L, Jones T W
University Program in Toxicology, University of Maryland, 660 W. Redwood Street, Baltimore, Maryland, 21201, USA.
Arch Biochem Biophys. 1996 Jul 15;331(2):225-31. doi: 10.1006/abbi.1996.0302.
A Ca2+-dependent inner mitochondrial membrane permeability transition is induced by a number of agents, an effect which is thought to cause cytotoxicity. This transition involves formation of a pore allowing the passage of solutes of up to 1500 Da; it is blocked by cyclosporine A and Ca2+ chelating agents. The mitochondrial nephrotoxicant S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine (PCBC) caused collapse of the mitochondrial membrane potential, Ca2+-independent oxidation of pyridine nucleotides and release of accumulated Ca2+ in isolated rat kidney mitochondria, three hallmarks of the permeability transition. These effects were blocked by cyclosporine A and by ethylene glycol bis(beta-aminoethyl ether) tetraacetic acid (EGTA). Furthermore, EGTA was capable of reversing the collapse of the membrane potential. These data indicate that PCBC induced an inner membrane permeability transition. Interestingly, addition of aminoxyacetic acid, a beta-lyase inhibitor, did not prevent the permeability transition, and a nonmetabolizable analog of PCBC, S-(1,2,3,4, 4-pentachlorobutadienyl)-L-alpha-methyl cysteine, induced the permeability transition. Thus PCBC may act to induce the permeability transition through a mechanism that does not require metabolism by a beta-lyase. Since metabolism by a beta-lyase is required for PCBC toxicity, it is not clear that the permeability transition is involved in cysteine conjugate-mediated renal cell injury.
多种因素可诱导钙离子依赖的线粒体内膜通透性转变，这种效应被认为会导致细胞毒性。这种转变涉及形成一个允许分子量高达1500道尔顿的溶质通过的孔道；它可被环孢素A和钙离子螯合剂阻断。线粒体肾毒物S-(1,2,3,4,4-五氯丁二烯基)-L-半胱氨酸（PCBC）可导致离体大鼠肾线粒体的线粒体膜电位崩溃、吡啶核苷酸的非钙离子依赖氧化以及累积钙离子的释放，这是通透性转变的三个标志。这些效应被环孢素A和乙二醇双(β-氨基乙醚)四乙酸（EGTA）阻断。此外，EGTA能够逆转膜电位的崩溃。这些数据表明PCBC诱导了内膜通透性转变。有趣的是，添加β-裂解酶抑制剂氨基氧乙酸并不能阻止通透性转变，并且PCBC的一种不可代谢类似物S-(1,2,3,4,4-五氯丁二烯基)-L-α-甲基半胱氨酸也能诱导通透性转变。因此，PCBC可能通过一种不需要β-裂解酶代谢的机制来诱导通透性转变。由于PCBC毒性需要β-裂解酶代谢，目前尚不清楚通透性转变是否参与半胱氨酸共轭物介导的肾细胞损伤。
