Ali Nemat, Rashid Summya, Nafees Sana, Hasan Syed Kazim, Shahid Ayaz, Majed Ferial, Sultana Sarwat
Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India.
Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India.
Chem Biol Interact. 2017 Jun 25;272:80-91. doi: 10.1016/j.cbi.2017.05.002. Epub 2017 May 4.
Methotrexate (MTX) is a drug which is used to treat different types of cancers but hepatotoxicity limits its clinical use. Chlorogenic acid (CGA) is one of the most abundant naturally occurring polyphenols in the human diet. Here, we assessed the effect of CGA against MTX-induced hepatotoxicity and investigated the underlying possible mechanisms in Wistar Rats. Rats were pre-treated with CGA (50 or 100 mg kg/b.w) and administered a single dose of MTX (20 mg/kg, b.w.). MTX caused hepatotoxicity as evidenced by significant increase in serum toxicity markers, histopathological changes. decreased activities of anti-oxidant armory (SOD, CAT, GPx, GR) and GSH content. MTX significantly causes upregulation of iNOS, Cox-2, Bax and downregulation of Bcl-2 expressions, it causes higher caspase 3, 9 activities. However CGA pretreatment alleviates the hepatotoxicity by decreasing the oxidative stress. CGA inhibited Cox-2, iNOS, Bax, Bcl-2 and Caspases 3, 9 mediated inflammation and apoptosis, and improve the histology induced by MTX. Thus, these findings demonstrated the hepatoprotective nature of CGA by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in hepatic tissue. These results imply that CGA has perfective effect against MTX-induced liver injury. Hence CGA supplementation might be helpful in abrogation of MTX toxicity.
甲氨蝶呤（MTX）是一种用于治疗不同类型癌症的药物，但肝毒性限制了其临床应用。绿原酸（CGA）是人类饮食中最丰富的天然多酚之一。在此，我们评估了CGA对MTX诱导的肝毒性的影响，并研究了Wistar大鼠潜在的可能机制。大鼠预先用CGA（50或100mg/kg体重）处理，然后给予单剂量的MTX（20mg/kg，体重）。MTX导致肝毒性，血清毒性标志物显著增加、组织病理学变化、抗氧化酶（超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶）活性降低以及谷胱甘肽含量下降均证明了这一点。MTX显著导致诱导型一氧化氮合酶、环氧化酶-2、Bax上调以及Bcl-2表达下调，导致半胱天冬酶3、9活性升高。然而，CGA预处理通过降低氧化应激减轻了肝毒性。CGA抑制环氧化酶-2、诱导型一氧化氮合酶、Bax、Bcl-2以及半胱天冬酶3、9介导的炎症和凋亡，并改善了MTX诱导的组织学变化。因此，这些发现证明了CGA通过减弱促炎和凋亡介质并提高肝组织中的抗氧化能力而具有肝脏保护作用。这些结果表明CGA对MTX诱导的肝损伤具有改善作用。因此，补充CGA可能有助于消除MTX的毒性。
