Al-Majed Abdulhakeem A, Sayed-Ahmed Mohamed M, Al-Yahya Abdulaziz A, Aleisa Abdulaziz M, Al-Rejaie Salim S, Al-Shabanah Othman A
Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Pharmacol Res. 2006 Mar;53(3):278-86. doi: 10.1016/j.phrs.2005.12.005. Epub 2006 Jan 24.
This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-L-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg(-1)), and d-carnitine (500 mg kg(-1)) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and D-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg(-1)). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO(x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO(x), and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.
开展本研究是为了调查内源性肉碱耗竭和/或肉碱缺乏是否是顺铂（CDDP）诱导的心肌病发生过程中的一个危险因素，若如此，通过左旋丙酰肉碱（PLC）补充肉碱是否可以预防这种毒性。为实现本研究的最终目标，将总共60只成年雄性Wistar白化大鼠分为六组。前三组分别连续10天腹腔注射生理盐水、PLC（500 mg kg⁻¹）和d - 肉碱（500 mg kg⁻¹）。第4、5和6组在单次注射CDDP（7 mg kg⁻¹）之前和之后分别连续5天腹腔注射相同剂量的生理盐水、PLC和D - 肉碱。在CDDP治疗后第6天，处死动物，分离血清和心脏并进行分析。CDDP导致血清肌酸磷酸激酶同工酶（CK - MB）、乳酸脱氢酶（LDH）、硫代巴比妥酸反应物质（TBARS）以及总硝酸盐/亚硝酸盐（NOₓ）显著增加，同时心脏组织中还原型谷胱甘肽（GSH）、总肉碱和三磷酸腺苷（ATP）含量显著降低。在肉碱耗竭的大鼠模型中，CDDP导致血清心肌病酶指标CK - MB和LDH显著升高，以及心脏组织中总肉碱和ATP含量逐渐降低。有趣的是，补充PLC导致由CDDP诱导的心脏酶、TBARS和NOₓ升高以及总肉碱、GSH和ATP降低完全逆转至对照值。此外，心脏组织的组织病理学检查证实了生化数据，其中PLC可预防CDDP诱导的心脏退行性变化，而d - 肉碱加剧了CDDP诱导的心脏组织损伤。总之，本研究数据首次表明肉碱缺乏和氧化应激是危险因素，应被视为CDDP相关心肌病发生过程中的机制，并且使用PLC补充肉碱可预防CDDP诱导的心脏毒性进展。
