Okkay Irmak Ferah, Famurewa Ademola, Bayram Cemil, Okkay Ufuk, Mendil Ali Sefa, Sezen Selma, Ayaz Teslime, Gecili Ibrahim, Ozkaraca Mustafa, Senyayla Selcuk, Hacimuftuoglu Ahmet
Pharmacology Department, Faculty of Pharmacy, Ataturk University, Ataturk Street, 25240, Yakutiye, Erzurum, Turkey.
Medical Biochemistry Department, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex-Ekwueme Federal University, Ndufu-Alike Ikwo, Abakaliki, Ebonyi State, Nigeria.
Toxicol Res (Camb). 2024 May 18;13(3):tfae075. doi: 10.1093/toxres/tfae075. eCollection 2024 Jun.
Cisplatin is a potent anticancer agent widely employed in chemotherapy. However, cisplatin leads to toxicity on non-targeted healthy organs, including the liver. We investigated the hepatoprotective mechanism of arbutin (ARB), a glycosylated hydroquinone, against cisplatin-induced hepatotoxicity.
Rats were orally administered with ARB (ARB1 = 50 mg/kg; ARB2 = 100 mg/kg) for 14 consecutive days against hepatotoxicity induced by a single dose of cisplatin (10 mg/kg) on day 15. Three days after the intraperitoneal cisplatin injection, serum and liver tissue were collected for subsequent analyses.
Cisplatin triggered marked increases in serum AST, ALT, and ALP activities, hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) coupled with a considerable diminution in hepatic activities of superoxide dismutase (SOD), catalase (CAT) and the concentration of reduced glutathione (GSH). The gene expressions of interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and IL-6 were notably increased. The pre-administration of ARB1 and ARB2 reduced AST, ALT and ALP in serum and restored SOD, CAT, GSH, ROS, MDA and cytokine levels which was also evidenced by alleviated hepatic lesions. Further, cisplatin-induced prominent alterations in the gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), iNOS, NF-κB, Bax, Bcl-2, caspase-3 and 8-OHdG in the liver. Interestingly, ARB protected the liver and mitigated the cisplatin-induced alterations in serum AST, ALT, ALP, and reduced hepatic redox markers, 8-OdG, inflammatory markers and gene expressions.
The findings demonstrate that ARB is a potential protective adjuvant against cisplatin-induced hepatotoxicity via inhibition of hepatic oxidative stress, inflammation, and apoptosis.
顺铂是一种在化疗中广泛应用的强效抗癌药物。然而，顺铂会对包括肝脏在内的非靶向健康器官产生毒性。我们研究了熊果苷（ARB），一种糖基化对苯二酚，对顺铂诱导的肝毒性的肝保护机制。
连续14天给大鼠口服ARB（ARB1 = 50 mg/kg；ARB2 = 100 mg/kg），以对抗第15天单次剂量顺铂（10 mg/kg）诱导的肝毒性。腹腔注射顺铂三天后，收集血清和肝组织用于后续分析。
顺铂引发血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和碱性磷酸酶（ALP）活性显著升高，肝丙二醛（MDA）和活性氧（ROS）增加，同时超氧化物歧化酶（SOD）、过氧化氢酶（CAT）的肝脏活性以及还原型谷胱甘肽（GSH）浓度显著降低。白细胞介素-1β（IL-1β）、肿瘤坏死因子（TNF-α）和IL-6的基因表达显著增加。预先给予ARB1和ARB2可降低血清中的AST、ALT和ALP，并恢复SOD、CAT、GSH、ROS、MDA和细胞因子水平，肝脏病变减轻也证明了这一点。此外，顺铂诱导肝脏中核因子红细胞2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）、诱导型一氧化氮合酶（iNOS）、核因子κB（NF-κB）、凋亡蛋白Bax、抗凋亡蛋白Bcl-2、半胱天冬酶-3和8-羟基脱氧鸟苷（8-OHdG）的基因表达发生显著改变。有趣的是，ARB保护肝脏并减轻了顺铂诱导的血清AST、ALT、ALP变化，降低了肝脏氧化还原标志物、8-氧代脱氧鸟苷（8-OdG）、炎症标志物和基因表达。
研究结果表明，ARB通过抑制肝脏氧化应激、炎症和凋亡，是一种潜在的对抗顺铂诱导肝毒性的保护佐剂。
