Harmon R Christopher, Kiningham Kinsley K, Valentovic Monica A
Department of Pharmacology, Marshall University Joan C. Edwards School of Medicine, 1542 Spring Valley Drive, Huntington, WV 25704-9388, USA.
Toxicol Appl Pharmacol. 2006 Jun 1;213(2):179-86. doi: 10.1016/j.taap.2005.10.008. Epub 2005 Dec 15.
Pyruvate has been observed to reduce the nephrotoxicity of some agents by maintaining glutathione status and preventing lipid peroxidation. This study examined the mechanism for pyruvate protection of p-aminophenol (PAP) nephrotoxicity. Renal cortical slices from male Fischer 344 rats were incubated for 30-120 min with 0, 0.1, 0.25 or 0.5 mM PAP in oxygenated Krebs buffer containing 0 or 10 mM pyruvate or glucose (1.28 or 5.5 mM). LDH leakage was increased above control by 0.25 and 0.5 mM PAP beginning at 60 min and by 0.1 mM PAP at 120 min. Pyruvate prevented an increase in LDH leakage at 60- and 120-min exposure to 0.1 and 0.25 mM PAP. Pyruvate also prevented a decline in ATP levels. Glucose (1.28 and 5.5 mM) provided less protection than pyruvate from PAP toxicity. Total glutathione levels were diminished by 0.1 and 0.25 mM PAP within 60 and 30 min, respectively. Pyruvate prevented the decline in glutathione by 0.1 mM PAP at both time periods and at 30 min for 0.25 mM PAP. Pyruvate reduced the magnitude of glutathione depletion by 0.25 mM PAP following a 60-min incubation. Glutathione disulfide (GSSG) levels in renal slices were increased at 60 min by exposure to 0.25 mM PAP, while pyruvate prevented increased GSSG levels by PAP. Pyruvate also reduced the extent of 4-hydroxynonenal (4-HNE)-adducted proteins present after a 90-min incubation with PAP. These results indicate that pyruvate provided protection for PAP toxicity by providing an energy substrate and reducing oxidative stress.
已观察到丙酮酸可通过维持谷胱甘肽水平和防止脂质过氧化来降低某些药物的肾毒性。本研究探讨了丙酮酸对扑热息痛（PAP）肾毒性的保护机制。将雄性Fischer 344大鼠的肾皮质切片在含有0或10 mM丙酮酸或葡萄糖（1.28或5.5 mM）的充氧Krebs缓冲液中与0、0.1、0.25或0.5 mM PAP孵育30 - 120分钟。从60分钟开始，0.25和0.5 mM PAP使乳酸脱氢酶（LDH）泄漏量高于对照组，120分钟时0.1 mM PAP也使其升高。丙酮酸可防止在60分钟和120分钟暴露于0.1和0.25 mM PAP时LDH泄漏量增加。丙酮酸还可防止ATP水平下降。葡萄糖（1.28和5.5 mM）对PAP毒性的保护作用不如丙酮酸。0.1和0.25 mM PAP分别在60分钟和30分钟内使总谷胱甘肽水平降低。丙酮酸在两个时间段均能防止0.1 mM PAP导致的谷胱甘肽下降，在30分钟时可防止0.25 mM PAP导致的下降。孵育60分钟后，丙酮酸可降低0.25 mM PAP导致的谷胱甘肽消耗程度。肾切片中谷胱甘肽二硫化物（GSSG）水平在60分钟时因暴露于0.25 mM PAP而升高，而丙酮酸可防止PAP导致的GSSG水平升高。丙酮酸还可减少与PAP孵育90分钟后出现的4 - 羟基壬烯醛（4 - HNE）加合物蛋白的程度。这些结果表明，丙酮酸通过提供能量底物和减轻氧化应激来保护机体免受PAP毒性。
