Mansour Heba H, El Kiki Shereen M, Galal Shereen M
Health Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt.
Arch Biochem Biophys. 2017 Feb 15;616:13-19. doi: 10.1016/j.abb.2017.01.005. Epub 2017 Jan 16.
Cisplatin (CIS) is a chemotherapeutic agent used for therapy of many tumors and has been limited by its toxicity. The aim of this study was to investigate the role of Peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B(NFB) in the pathogenesis of hepatic damage induced by CIS, and investigated the modulatory effect of metformin (MET) and/or low dose gamma radiation (LDR) on CIS-induced hepatotoxicity in rats. CIS(7.5 mg/kg, i.p.) hepatotoxicity was evidenced by alteration of serum hepatic indices (ALT and AST) accompanied with decreased hepatic PPAR-γ, superoxide dismutase (SOD) activities and reduced glutathione (GSH) content, whereas the levels of malondialdehyde (MDA), total nitrate/nitrite (NOx) and NFB significantly increased as well as MAPK activity compared with the control, MET and LDR groups. Furthermore, CIS induces apoptosis as indicated by an elevation of hepatic caspase-3. Treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy), prior to CIS alleviates CIS-induced hepatic damage by mitigating oxidative/ nitrosative stress and PPAR-γ activity reduction, hepatic caspase-3 elevation, and inhibition of NFκB, and MAPK activity levels.
Modulation of PPAR-γ, MAPK and NFB might contribute to amelioration of CIS-induced hepatic toxicity.
顺铂（CIS）是一种用于治疗多种肿瘤的化疗药物，但其毒性限制了其应用。本研究旨在探讨过氧化物酶体增殖物激活受体γ（PPAR-γ）、丝裂原活化蛋白激酶（MAPK）和核因子κB（NFκB）在顺铂诱导的肝损伤发病机制中的作用，并研究二甲双胍（MET）和/或低剂量γ辐射（LDR）对顺铂诱导的大鼠肝毒性的调节作用。顺铂（7.5mg/kg，腹腔注射）导致的肝毒性表现为血清肝指标（ALT和AST）改变，同时肝PPAR-γ、超氧化物歧化酶（SOD）活性降低以及还原型谷胱甘肽（GSH）含量减少，而与对照组、MET组和LDR组相比，丙二醛（MDA）、总硝酸盐/亚硝酸盐（NOx）水平以及NFκB和MAPK活性显著升高。此外，顺铂诱导肝caspase-3升高，表明诱导了细胞凋亡。在顺铂给药前给予MET（150mg/kg，口服14天）和/或LDR（0.5Gy），可通过减轻氧化/亚硝化应激和PPAR-γ活性降低、肝caspase-3升高以及抑制NFκB和MAPK活性水平来减轻顺铂诱导的肝损伤。
调节PPAR-γ、MAPK和NFκB可能有助于改善顺铂诱导的肝毒性。
