Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea; College of Pharmacy, Jeju Research Institute of Pharmaceutical Sciences, Jeju National University, Jeju, Republic of Korea.
Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
J Nutr Biochem. 2022 Oct;108:109082. doi: 10.1016/j.jnutbio.2022.109082. Epub 2022 Jun 10.
Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CβS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.
饮食限制（DR）已被证明具有健康益处，因为它可降低氧化应激。由于 DR，啮齿动物肝脏中的谷胱甘肽（GSH）增加，这是一种重要的细胞抗氧化剂；然而，DR 的确切机制和临床相关性尚未完全理解。在这项研究中，雄性 C57BL/6 小鼠接受了 50%的限制饮食 7 天，测定肝脏含硫氨基酸（SAA）代谢以评估 GSH 的生物合成。由于贝叶因同型半胱氨酸甲基转移酶（BHMT）减少和 CβS、CγL 和谷氨酸半胱氨酸连接酶催化亚基（GCLC）蛋白增加，导致肝脏中蛋氨酸水平降低，而同型半胱氨酸、半胱氨酸和 GSH 水平增加。为了确定 DR 对药物诱导的氧化肝损伤的影响，对 DR 小鼠注射了有毒剂量（300mg/kg）的对乙酰氨基酚（APAP）。DR 显著减轻了 APAP 诱导的肝损伤和氧化应激，这可能归因于肝脏中 GSH 和相关抗氧化酶（GPx、GSTα和 GSTµ）水平较高。肝脏 CYP1A、2E1 和 3A 水平降低，暗示 APAP 代谢活化的抑制，可能导致 DR 小鼠的肝毒性降低。总的来说，我们的研究结果表明，DR 刺激了肝脏转硫途径和 GSH 合成。因此，GSH 的升高可以作为 DR 介导的 APAP 中毒肝脏保护的重要机制。
