药物性肝损伤指在用药过程中药物与肝脏直接或间接作用对肝脏所产生的毒害作用。其发生与年龄、性别、肥胖、饮酒、自身营养状况等有关，尤其合并有肝脏基础疾病时会增加用药风险。扑热息痛(acetaminophen，APAP)，又名对乙酰氨基酚，非那西丁的活性代谢产物，为常用解热镇痛药物之一。常规剂量扑热息痛是相对安全的，但在长期和(或)过量使用的情况下，易造成肝中心小叶坏死．严重者发展为急性肝功能衰竭。在英美等国家，APAP是导致急性肝衰竭的主要原因，我国也比较常见。

有研究发现，氧化应激在扑热息痛诱导肝损伤发生过程中发挥重要作用，细胞内线粒体和细胞外炎症细胞来源的活性氧是导致肝细胞损伤的重要原因，许多抗氧化物质具有预防扑热息痛诱导肝损伤的效果。另外炎症反应也是扑热息痛诱导肝损伤的重要因素，在这种损伤过程中，一些炎症因子明显增加，中和肿瘤坏死因子和白细胞介素1等炎症因子的作用能减轻肝损伤的发生。某些蛋白酶如细胞色素P4502E、诱导型一氧化氮合成酶和JNK信号分子也参与扑热息痛诱导肝损伤的病理过程。最近研究发现，细胞之间直接信息通道缝隙连接在药物诱导肝损伤的发生发展过程中也十分重要。缝隙连接蛋白32（Cx32）是肝脏内缝隙连接的最主要类型，具有促进药物诱导肝损伤的作用。Patel等发现，小鼠缺乏Cx32能耐受硫代乙酰胺诱导的肝损伤。药物阻断Cx32能缓解硫代乙酰胺或扑热息痛诱导的肝损伤。

分子氢是宇宙中质量最小的气体分子，研究发现氢气具有多种治疗疾病的效果，其主要作用方式是具有抗氧化抗炎症和抗细胞碉亡等效应。过去研究曾经发现，氢气治疗肝脏疾病包括肝脏组织缺血再灌注损伤、Con A诱导的肝脏炎症反应、血吸虫病导致的肝脏损伤和非酒精性肝硬化等，但是氢气对扑热息痛诱导的肝损伤尚未见报道。氢气水是一种方便经济的给氢方法，具有和呼吸氢气类似的效果，目前已经作为一种健康产品受到大众的欢迎，也有许多研究希望尝试将氢水作为治疗疾病的手段。最新来自西安交通大学第一附属医院肝脏外科Chang Liu小组对氢气治疗扑热息痛诱导的肝损伤进行了系统研究，证明氢水这是一种有效预防扑热息痛诱导的肝损伤的方法，论文最近在线发表在世界胃肠杂志上。

Schematic representation of the proposed effect of the hydrogen molecule in acetaminophen-induced hepatic injury.

研究证明氢水能减少扑热息痛诱导肝脏组织的氧化损伤和炎症反应，缓解肝脏组织病理改变包括超微结构的变化，保护肝脏功能，能促进肝脏细胞的再生能力，这些作用可能于抑制缝隙连接蛋白Cx32，抑制细胞内信号分子JNK活性有关。

作者信息: Chang Liu, MD, PhD, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, Shaanxi Province, China. liuchangdoctor@163.com

AIM: To investigate the hepatoprotective effects and mechanisms of hydrogen-rich water (HRW) in acetaminophen (APAP)-induced liver injury in mice.

METHODS: Male mice were randomly divided into the following four groups: normal saline (NS) control group, mice received equivalent volumes of NS intraperitoneally (ip); HRW control group, mice were given HRW (same volume as the NS group); APAP + NS group, mice received NS ip for 3 d (5 mL/kg body weight, twice a day at 8 am and 5 pm) after APAP injection; APAP + HRW group, mice received HRW for 3 d (same as NS treatment) after APAP challenge. In the first experiment, mice were injected ip with a lethal dose of 750 mg/kg APAP to determine the 5-d survival rates. In the second experiment, mice were injected ip with a sub-lethal dose of 500 mg/kg. Blood and liver samples were collected at 24, 48, and 72 h after APAP injection to determine the degree of liver injury.

RESULTS: Treatment with HRW resulted in a significant increase in the 5-d survival rate compared with the APAP + NS treatment group (60% vs 26.67%, P < 0.05). HRW could significantly decrease the serum alanine aminotransferase level (24 h: 4442 ± 714.3 U/L vs 6909 ± 304.8 U/L, P < 0.01; 48 h: 3782 ± 557.5 U/L vs 5111 ± 404 U/L, P < 0.01; and 3255 ± 337.4 U/L vs 3814 ± 250.2 U/L, P < 0.05, respectively) and aspartate aminotransferase level (24 h: 4683 ± 443.4 U/L vs 5307 ± 408.4 U/L, P < 0.05; 48 h: 3392 ± 377.6 U/L vs 4458 ± 423.6 U/L, P < 0.01; and 3354 ± 399.4 U/L vs 3778 ± 358 U/L, respectively) compared with the APAP treatment group. The alkaline phosphatase, total bilirubin and lactate dehydrogenase levels had the same result. Seventy-two hours after APAP administration, liver samples were collected for pathological examination and serum was collected to detect the cytokine levels. The liver index (5.16% ± 0.26% vs 5.88% ± 0.073%, P < 0.05) and percentage of liver necrosis area (27.73% ± 0.58% vs 36.87% ± 0.49%, P < 0.01) were significantly lower in the HRW-treated animals. The malonyldialdehyde (MDA) contents were significantly reduced in the HRW pretreatment group, but they were increased in the APAP-treated group (10.44 ± 1.339 nmol/mg protein vs 16.70 ± 1.646 nmol/mg protein, P < 0.05). A decrease in superoxide dismutase (SOD) activity in the APAP treatment group and an increase of SOD in the HRW treatment group were also detected (9.74 ± 0.46 U/mg protein vs 12.1 ± 0.67 U/mg protein, P < 0.05). Furthermore, HRW could significantly increase the glutathione (GSH) contents (878.7 ± 76.73 mg/g protein vs 499.2 ± 48.87 mg/g protein) compared with the APAP treatment group. Meanwhile, HRW could reduce the inflammation level (serum TNF-α: 399.3 ± 45.50 pg/L vs 542.8 ± 22.38 pg/L, P < 0.05; and serum IL-6: 1056 ± 77.01 pg/L vs 1565 ± 42.11 pg/L, P < 0.01, respectively). In addition, HRW could inhibit 4-HNE, nitrotyrosine formation, JNK phosphorylation, connexin 32 and cytochrome P4502E expression. Simultaneously, HRW could facilitate hepatocyte mitosis to promote liver regeneration.

CONCLUSION: HRW has significant therapeutic potential in APAP-induced hepatotoxicity by inhibiting oxidative stress and inflammation and promoting liver regeneration.

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