Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues.
Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues.
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DOI：
10.4161/oxim.3.5.13107
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发表时间：
2010-09
影响因子：
--
通讯作者：
Asiri YA
中科院分区：
文献类型：
--
作者：
Asiri YA
环磷酰胺（Cyclophosphamide，CP）是一种广泛应用于肿瘤化疗和免疫抑制的药物，其代谢产物具有毒性，可对正常细胞产生毒性作用。普罗布考是一种降胆固醇药物，可作为DNA损伤的潜在抑制剂，并通过增强内源性抗氧化系统（包括谷胱甘肽过氧化物酶、过氧化氢酶和超氧化物歧化酶）来预防阿霉素诱导的心肌病。本研究探讨了普罗布考（一种具有强抗氧化特性的降脂化合物）对CP诱导的心脏毒性的可能保护作用。这一目的可以通过研究基因表达来实现-基于普罗布考对CP诱导的大鼠心力衰竭的可能保护作用。将成年雄性Wistar白化病大鼠分为四个治疗组：第一组（对照）和第二组（普罗布考）分别腹腔注射玉米油和普罗布考（61 mg/kg/天），持续两周。在第三组（CP）和第四组（普罗布考加CP）中的动物分别注射相同剂量的玉米油和普罗布考（61 mg/kg/天），在单次CP给药（200 mg/kg，腹膜内）之前和之后一周。真实的时间PCR检测p53、Bax、Bcl 2和氧化相关基因的表达。与对照组相比，通过血清肌酸磷酸激酶同工酶（CK-MB）（117%）、乳酸脱氢酶（LDH）（64%）、游离胆固醇（69%）、酯化胆固醇（42%）和甘油三酯（69%）的显著增加，明确观察到CP诱导的心脏毒性。在心肌组织中，CP显著增加凋亡基因的mRNA表达水平，p53增加2倍，Bax增加1.6倍，而抗凋亡基因Bcl 2减少0.5倍。此外，CP引起抗氧化基因，谷胱甘肽过氧化物酶，过氧化氢酶和超氧化物歧化酶的下调，增加脂质过氧化和降低三磷酸腺苷（ATP）（40%）和ATP/ADP（44%）在心脏组织中。普罗布考预处理不仅能显著对抗CP诱导的心肌酶升高和细胞凋亡，还能诱导心肌组织中抗氧化酶mRNA表达显著增加，ATP、ATP/ADP、谷胱甘肽（GSH）水平显著提高。总之，本研究的数据表明，普罗布考防止CP诱导的心脏毒性的发展相关的机制，至少部分地，其能力，以增加抗氧化基因的mRNA表达和减少心肌组织的细胞凋亡，从而改善线粒体氧化磷酸化和能源生产。
Cyclophosphamide (CP) is a widely used drug in cancer chemotherapy and immunosuppression, which could cause toxicity of the normal cells due to its toxic metabolites. Probucol, a cholesterol-lowering drug, acts as potential inhibitor of DNA damage and shows to protect against doxorubicin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase. This study examined the possible protective effects of probucol, a lipid-lowering compound with strong antioxidant properties, against CPinduced cardiotoxicity. This objective could be achieved through studying the gene expression-based on the possible protective effects of probucol against CP-induced cardiac failure in rats. Adult male Wistar albino rats were assigned into four treatment groups: Animals in the first (control) and second (probucol) groups were injected intraperitoneally with corn oil and probucol (61 mg/kg/day), respectively, for two weeks. Animals in the third (CP) and fourth (probucol plus CP) groups were injected with the same doses of corn oil and probucol (61 mg/kg/day), respectively, for one week before and one week after a single dose of CP (200 mg/kg, I.P.). The p53, Bax, Bcl2 and oxidative genes signal expression were measured by real time PCR. CP-induced cardiotoxicity was clearly observed by a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) (117%), lactate dehydrogenase (LDH) (64%), free (69%) and esterified cholesterol (42%) and triglyceride (69%) compared to control group. In cardiac tissues, CP significantly increases the mRNA expression levels of apoptotic genes, p53 with two-fold and Bax with 1.6-fold, and decreases the anti-apoptotic gene Bcl2 with 0.5-fold. Moreover, CP caused downregulation of antioxidant genes, glutathione peroxidase, catalase, and superoxide dismutase and increased the lipid peroxidation and decreased adenosine triphosphate (ATP) (40%) and ATP/ADP (44%) in cardiac tissues. Probucol pretreatment not only counteracted significantly the CP-induced increase in cardiac enzymes and apoptosis but also induced a significant increase in mRNA expression of antioxidant enzymes and improved ATP, ATP/ADP, glutathione (GSH) in cardiac tissues. In conclusion, data from the present study suggest that probucol prevents the development of CP-induced cardiotoxicity by a mechanism related, at least in part, to its ability to increase mRNA expression of antioxidant genes and to decrease apoptosis in cardiac tissues with the consequent improvement in mitochondrial oxidative phosphorylation and energy production.
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