Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats
Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats
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DOI：
10.1111/j.1742-7843.2006.00024.x
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发表时间：
2007-03-01
影响因子：
3.1
通讯作者：
Al-Majed, Abdulhakeem A.
中科院分区：
文献类型：
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作者：
Al-Majed, Abdulhakeem A.
本研究调查肉碱缺乏是否是一个危险因素，并可能导致顺铂引起的肝毒性。总共60只成年雄性Wistar白化大鼠分为六组。前三组分别腹腔注射生理盐水、丙酰左旋肉碱(500mg/kg)、D-肉碱(500mg/kg)，连续10天。第四组、第五组和第六组在单次顺铂（7mg/kg）前后连续5天分别腹腔注射等剂量的生理盐水、丙酰左旋肉碱和D-肉碱。给予标准肾毒性剂量的顺铂不会导致血清丙氨酸转氨酶和γ-谷氨酰转移酶发生任何变化，肝组织也没有发生形态学变化。然而，它确实使肝组织中硫代巴比妥酸反应物质和总硝酸盐/亚硝酸盐显着增加，并显着降低还原型谷胱甘肽含量。另一方面，顺铂和D-肉碱联合治疗导致血清丙氨酸转氨酶和γ-谷氨酰转移酶显着升高，以及肝组织中总肉碱和ATP含量逐渐减少。此外，肝组织的组织病理学检查证实了生化数据，其中顺铂和D-肉碱组合显示出肝损伤的迹象，表现为局灶性坏死性炎症变化和门静脉炎症。有趣的是，在使用丙酰-L-肉碱补充肉碱的大鼠中，顺铂没有在肝组织中产生任何生化和组织病理学变化。总之，这项研究的数据首次表明（1）肉碱缺乏是一个危险因素，可能会引发顺铂引起的肝毒性，（2）氧化应激不是顺铂相关肝毒性的主要原因，（3）丙酰-L-肉碱可预防顺铂引起的肝损伤的发展。
This study investigates whether or not carnitine deficiency is a risk factor and could contribute to cisplatin-induced liver toxicity. A total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, propionyl-L-carnitine (500 mg/kg), and D-carnitine (500 mg/kg), respectively, for 10 successive days. The fourth, fifth and sixth groups were injected intraperitoneally with the same doses of normal saline, propionyl-L-carnitine and D-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Administration of the standard nephrotoxic dose of cisplatin did not produce any changes in serum alanine transaminase and gamma-glutamyl transferase and no morphological changes in liver tissues. However, it did produce a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione content in liver tissues. On the other hand, combined treatment with cisplatin and D-carnitine induced a dramatic increase in serum alanine transaminase and gamma-glutamyl transferase, as well as progressive reduction in total carnitine and ATP content in liver tissue. Moreover, histopathological examination of liver tissues confirmed the biochemical data, where cisplatin and D-carnitine combination showed signs of liver injury manifested as focal necro-inflammatory changes and portal inflammation. Interestingly, in carnitine supplemented rats using propionyl-L-carnitine, cisplatin did not produce any biochemical and histopathological changes in liver tissues. In conclusion, data from this study suggest for the first time that (1) carnitine deficiency is a risk factor and could precipitate cisplatin-induced hepatotoxicity, (2) oxidative stress is not the main cause of cisplatin-related hepatotoxicity and (3) propionyl-L-carnitine prevents the development of cisplatin-induced liver injury.