MITOCHONDRIAL DYSFUNCTION IS AN EARLY EVENT IN OCHRATOXIN-A BUT NOT OOSPOREIN TOXICITY TO RAT RENAL PROXIMAL TUBULES
MITOCHONDRIAL DYSFUNCTION IS AN EARLY EVENT IN OCHRATOXIN-A BUT NOT OOSPOREIN TOXICITY TO RAT RENAL PROXIMAL TUBULES
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DOI：
10.1016/0041-008x(91)90332-9
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发表时间：
1991-01-01
影响因子：
3.8
通讯作者：
SCHNELLMANN, RG
中科院分区：
文献类型：
--
作者：
ALEO, MD;WYATT, RD;SCHNELLMANN, RG
赭曲霉毒素A （OA）和卵孢子素（OSN）是两种真菌毒素，可通过线粒体功能障碍或脂质过氧化引起肾毒性。用离体大鼠肾近端小管悬浮液，研究OA或osn诱导的细胞毒性前的细胞事件。OA和OSN以浓度（0-1 mm）和时间（0-4小时）依赖的方式降低小管活力，暴露后1小时开始下降。暴露于OA（0.5和1 mm）和0.25 mmt-丁基过氧化氢（TBHP）后，细胞死亡前小管基础和制氨抑素刺激的耗氧量减少，但暴露于OSN （0.25 - 1 mm）后没有减少。在这些研究中，氧化剂三必拓被用作阳性对照。对近端小管线粒体功能的直接探测证实了OA对线粒体的毒性。在暴露于1mm OA后15和30分钟，通过I位点（谷氨酸/苹果酸）和II位点（琥珀酸）呼吸底物，在缺乏和存在磷酸盐受体的情况下，呼吸作用减少。脂质过氧化在暴露于1mm OA和0.25 mm TBHP后导致细胞死亡，但暴露于1mm OSN后未发生。在加入1 mm OA或OSN之前，去铁胺（1 mm）预处理可阻止OA诱导的脂质过氧化，但不能阻止OA或OSN诱导的细胞毒性。相比之下，去铁胺预处理可以防止脂质过氧化、线粒体功能障碍和暴露于0.25 mm TBHP后小管活力的丧失。这项研究表明，线粒体功能障碍是OA毒性发展的早期事件，但不是osn诱导的毒性。此外，铁介导的脂质过氧化不会导致OA或osn诱导的近端小管细胞死亡。
Ochratoxin A (OA) and oosporein (OSN) are two mycotoxins that may cause nephrotoxicity through either mitochondrial dysfunction or lipid peroxidation. Using isolated rat renal proximal tubules in suspension, the cellular events preceding OA- or OSN-induced cytotoxicity were investigated. OA and OSN decreased tubule viability in a concentration (0–1 mm)- and time (0–4 hr)-dependent manner, with initial decreases occurring 1 hr after exposure. Tubule basal and nystatin-stimulated oxygen consumption decreased before cell death after OA (0.5 and 1 mm) and 0.25 mmt-butyl hydroperoxide (TBHP) exposure, but did not decrease after OSN exposure (0.25–1 mm). The oxidant TBHP was used as a positive control in these studies. Direct probing of mitochondrial function within proximal tubules confirmed the toxicity of OA to mitochondria. Respiration was reduced in the absence and presence of a phosphate acceptor using site I (glutamate/malate) and site II (succinate) respiratory substrates 15 and 30 min after exposure to 1 mm OA. Lipid peroxidation preceded cell death after exposure to 1 mm OA and 0.25 mm TBHP, but did not occur after exposure to 1 mm OSN. Deferoxamine (1 mm) pretreatment before the addition of 1 mm OA or OSN prevented OA-induced lipid peroxidation, but did not prevent OA- or OSN-induced cytotoxicity. In contrast, deferoxamine pretreatment prevented lipid peroxidation, mitochondrial dysfunction, and the loss of tubule viability after exposure to 0.25 mm TBHP. This study shows that mitochondrial dysfunction is an early event during the development of OA toxicity, but not in OSN-induced toxicity. Furthermore, iron-mediated lipid peroxidation does not contribute to OA- or OSN-induced proximal tubule cell death.