Abo-El-Sooud Khaled, Hesham Hagar, Saeed Maryam, Mohamed Sarah, Youssef Fady Sayed
Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
Sci Rep. 2025 Aug 24;15(1):31104. doi: 10.1038/s41598-025-16453-z.
Liver injury is a globally serious problem that may be observed post-chemotherapeutic administration in chronic crises such as tuberculosis (TB). Rifamycin (RIF), particularly, is an indispensable treatment regimen for TB with a significant negative hepatic impact. Therefore, this research aims to assess the restorative role of melatonin (MEL) against rifampicin (RIF)-associated hepatic damage in rats. Moreover, to investigate the ultimate mechanism of the antioxidant potential of MEL with multimodal assessment and in silico molecular conformation. Adult male Wistar albino rats were weighed and divided into four groups of ten rats each. The control group received the vehicle (0.5 ml/day), the RIF-intoxicated group (100 mg/kg/day orally), the MEL-treated group (10 mg/kg/day intraperitoneally), and the Co-administered RIF and MEL group at the same regimen for 21 consecutive days. Blood and hepatic tissue samples were obtained for biochemical, histological, and molecular studies. High in vitro antioxidant scavenging potential of MEL with an IC of 94.66 µg/ml was attained using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Fourier transform infrared spectroscopy (FTIR) and gas chromatography-mass spectrometry (GC-MS) analyses of MEL indicated the presence of mainly cinnamic acid, m-(trimethyl-silyl ester), in addition to several reactive antioxidant moieties. The plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lipid profiles were significantly reduced in the MEL + RIF co-administered group in contrast to the RIF-treated group (P < 0.05). Moreover, MEL significantly decreased the hepatic oxidative biomarkers malondialdehyde (MDA) and significantly increased the estimated antioxidant enzyme levels (P < 0.05) of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Histological evaluations revealed mild hepatic injuries and inflammatory cellular infiltration in MEL-treated animals. Molecular docking explored the high-affinity interaction of MEL and cinnamic acids with hepatic cytochrome P450 isoform 3A4 (CYP3A4) protein target, confirming their hepatic restorative potential. This study endorses the antioxidant potential role of MEL in RIF-hepatic injury.
肝损伤是一个全球性的严重问题，在结核病（TB）等慢性疾病化疗后可能会出现。特别是利福霉素（RIF），是结核病不可或缺的治疗方案，但对肝脏有显著的负面影响。因此，本研究旨在评估褪黑素（MEL）对大鼠利福平（RIF）相关肝损伤的修复作用。此外，通过多模态评估和计算机模拟分子构象研究MEL抗氧化潜力的最终机制。将成年雄性Wistar白化大鼠称重并分为四组，每组十只。对照组给予溶媒（0.5毫升/天），RIF中毒组（口服100毫克/千克/天），MEL治疗组（腹腔注射10毫克/千克/天），以及RIF和MEL联合给药组，按相同方案连续给药21天。采集血液和肝脏组织样本进行生化、组织学和分子研究。使用2,2-二苯基-1-苦基肼（DPPH）法测定，MEL的体外抗氧化清除潜力较高，半数抑制浓度（IC）为94.66微克/毫升。对MEL进行傅里叶变换红外光谱（FTIR）和气相色谱-质谱（GC-MS）分析表明，除了几个活性抗氧化部分外，主要存在肉桂酸、间（三甲基硅基酯）。与RIF治疗组相比，MEL+RIF联合给药组的天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、碱性磷酸酶（ALP）血浆水平和血脂谱显著降低（P<0.05）。此外，MEL显著降低肝脏氧化生物标志物丙二醛（MDA），并显著提高超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPX）的估计抗氧化酶水平（P<0.05）。组织学评估显示，MEL治疗的动物有轻度肝损伤和炎性细胞浸润。分子对接研究了MEL和肉桂酸与肝细胞色素P450同工酶3A4（CYP3A4）蛋白靶点的高亲和力相互作用，证实了它们的肝脏修复潜力。本研究支持MEL在RIF肝损伤中的抗氧化潜在作用。
