Kalayarasan Srinivasan, Prabhu Ponnuraj Nagendra, Sriram Narayanan, Manikandan Ramar, Arumugam Munusamy, Sudhandiran Ganapasam
Department of Biochemistry, University of Madras, Guindy campus, Chennai, Tamil nadu, India.
Eur J Pharmacol. 2009 Mar 15;606(1-3):162-71. doi: 10.1016/j.ejphar.2008.12.055. Epub 2009 Jan 19.
The protective role of diallyl sulfide (DAS) in attenuating gentamicin-induced nephrotoxicity has been reported earlier. However, the mechanism of induction of antioxidants by DAS in nephrotoxicity remains elusive. This study is aimed to elucidate the role of a transcription factor, Nuclear factor E2-related factor 2 (Nrf2) in inducing antioxidants and phase II enzymes during gentamicin toxicity in Wistar rats. DAS was administered intraperitoneally at a dosage of 150 mg/kg body weight once daily for 6 days. Gentamicin was administered intraperitoneally at a dosage of 100 mg/kg body weight, once daily for 6 days. Gentamicin-induced rats showed a significant increase in the levels of kidney markers and the activities of urinary marker enzymes, which was reversed upon treatment with DAS. A significant increase in kidney myeloperoxidase (MPO) and lipid peroxidation (LPO) levels was observed in gentamicin-induced rats, which was reduced upon treatment with DAS. Gentamicin-induced rats also showed a significant decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and quinone reductase (QR) in rat kidney, which was increased upon treatment with DAS. Immunohistochemical studies in gentamicin-induced rats demonstrated a marked increase in the immunoreactivity of inducible nitric oxide synthase (iNOS), nuclear transcription factor (NF-kappaB) and tumor necrosis factor alpha (TNF-alpha) that were reduced after treatment with DAS. Further, the involvement of Nrf2 in antioxidant induction was analyzed by Western blot and immunofluorescence. To conclude, DAS enhances antioxidants and suppresses inflammatory cytokines through the activation of Nrf2, thereby protecting the cell against oxidative stress induced by gentamicin.
二烯丙基硫醚（DAS）在减轻庆大霉素诱导的肾毒性方面的保护作用此前已有报道。然而，DAS在肾毒性中诱导抗氧化剂的机制仍不清楚。本研究旨在阐明转录因子核因子E2相关因子2（Nrf2）在Wistar大鼠庆大霉素毒性期间诱导抗氧化剂和II期酶中的作用。DAS以150mg/kg体重的剂量腹腔注射，每日一次，共6天。庆大霉素以100mg/kg体重的剂量腹腔注射，每日一次，共6天。庆大霉素诱导的大鼠肾脏标志物水平和尿标志物酶活性显著增加，而DAS治疗后则逆转。在庆大霉素诱导的大鼠中观察到肾脏髓过氧化物酶（MPO）和脂质过氧化（LPO）水平显著增加，而DAS治疗后则降低。庆大霉素诱导的大鼠肾脏中超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPx）、谷胱甘肽还原酶（GR）、谷胱甘肽-S-转移酶（GST）和醌还原酶（QR）的活性也显著降低，而DAS治疗后则增加。对庆大霉素诱导的大鼠进行免疫组织化学研究表明，诱导型一氧化氮合酶（iNOS）、核转录因子（NF-κB）和肿瘤坏死因子α（TNF-α）的免疫反应性显著增加，而DAS治疗后则降低。此外，通过蛋白质免疫印迹和免疫荧光分析了Nrf2在抗氧化剂诱导中的作用。总之，DAS通过激活Nrf2增强抗氧化剂并抑制炎性细胞因子，从而保护细胞免受庆大霉素诱导的氧化应激。
