Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia.
Nephrol Dial Transplant. 2010 Jan;25(1):69-76. doi: 10.1093/ndt/gfp457. Epub 2009 Sep 8.
This study examined whether carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of gentamicin (GM)-induced ARF as well as exploring if carnitine supplementation could offer protection against this toxicity.
Adult male Wistar albino rats were assigned to one of six treatment groups: group 1 (control) rats were given daily intraperitoneal (I.P.) injections of normal saline for 8 consecutive days; groups 2, 3 and 4 rats were given GM (80 mg/kg/day, I.P.), l-carnitine (200 mg/kg/day, I.P.) and d-carnitine (250 mg/kg/day, I.P.), respectively, for 8 consecutive days. Rats of group 5 (GM plus d-carnitine) received a daily I.P. injection of d-carnitine (250 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days. Rats of group 6 (GM plus l-carnitine) received a daily I.P. injection of l-carnitine (200 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days.
GM significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion, intramitochondrial acetyl-CoA and total nitrate/nitrite (NOx) and thiobarbituric acid reactive substances (TBARS) in kidney tissues and significantly decreased total carnitine, intramitochondrial CoA-SH, ATP, ATP/ADP and reduced glutathione (GSH) in kidney tissues. In carnitine-depleted rats, GM caused a progressive increase in serum creatinine, BUN and urinary carnitine excretion and a progressive decrease in total carnitine, intamitochondrial CoA-SH and ATP. Interestingly, l-carnitine supplementation resulted in a complete reversal of the increase in serum creatinine, BUN, urinary carnitine excretion and the decrease in total carnitine, intramitochondrial CoA-SH and ATP, induced by GM, to the control values. Moreover, the histopathological examination of kidney tissues confirmed the biochemical data, where l-carnitine prevents and d-carnitine aggravates GM-induced ARF.
(i) GM-induced nephrotoxicity leads to increased urinary losses of carnitine; (ii) carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of GM-induced ARF; and (iii) carnitine supplementation ameliorates the severity of GM-induced kidney dysfunction by increasing the intramitochondrial CoA-SH/acetyl-CoA ratio and ATP production.
本研究旨在探讨肉碱缺乏是否是庆大霉素（GM）诱导急性肾损伤（ARF）发生的危险因素，以及肉碱补充是否可以对此毒性起到保护作用。
成年雄性 Wistar 白化大鼠被分为六组治疗组之一：第 1 组（对照组）大鼠连续 8 天每天接受腹腔内（I.P.）注射生理盐水；第 2、3 和 4 组大鼠分别连续 8 天接受 GM（80mg/kg/天，I.P.）、左旋肉碱（200mg/kg/天，I.P.）和右肉碱（250mg/kg/天，I.P.）治疗。第 5 组（GM 加右肉碱）大鼠连续 8 天在接受 GM（80mg/kg/天）前 1 小时接受右肉碱（250mg/kg/天，I.P.）的每日 I.P.注射。第 6 组（GM 加左旋肉碱）大鼠连续 8 天在接受 GM（80mg/kg/天）前 1 小时接受左旋肉碱（200mg/kg/天，I.P.）的每日 I.P.注射。
GM 显著增加血清肌酐、血尿素氮（BUN）、尿肉碱排泄、线粒体乙酰辅酶 A 和总硝酸盐/亚硝酸盐（NOx）和硫代巴比妥酸反应物质（TBARS）在肾脏组织中，并显著降低肾脏组织中的总肉碱、线粒体 CoA-SH、ATP、ATP/ADP 和还原型谷胱甘肽（GSH）。在肉碱耗竭的大鼠中，GM 导致血清肌酐、BUN 和尿肉碱排泄逐渐增加，总肉碱、线粒体内 CoA-SH 和 ATP 逐渐减少。有趣的是，左旋肉碱补充完全逆转了 GM 引起的血清肌酐、BUN、尿肉碱排泄和总肉碱、线粒体内 CoA-SH 和 ATP 的增加，使其恢复到对照值。此外，肾脏组织的组织病理学检查证实了生化数据，其中左旋肉碱可预防，而右肉碱可加重 GM 诱导的 ARF。
（i）GM 诱导的肾毒性导致尿肉碱丢失增加；（ii）肉碱缺乏是 GM 诱导 ARF 发生的危险因素，应视为一种机制；（iii）肉碱补充通过增加线粒体内 CoA-SH/乙酰辅酶 A 比值和 ATP 产生来改善 GM 诱导的肾功能障碍的严重程度。
