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Valproic acid induced liver injury: An insight into molecular toxicological mechanism
Environmental Toxicology and Pharmacology ( IF 4.3 ) Pub Date : 2022-09-01 , DOI: 10.1016/j.etap.2022.103967
Devaraj Ezhilarasan 1 , Uthirappan Mani 2
Affiliation  

Valproic acid (VPA) is an anti-seizure drug that causes idiosyncratic liver injury. 2-propyl-4-pentenoic acid (Δ4VPA), a metabolite of VPA, has been implicated in VPA-induced hepatotoxicity. This review summarizes the pathogenesis involved in VPA-induced liver injury. The VPA induce liver injury mainly by i) liberation of Δ4VPA metabolites; ii) decrease in glutathione stores and antioxidants, resulting in oxidative stress; iii) inhibition of fatty acid β-oxidation, inducing mitochondrial DNA depletion and hypermethylation; a decrease in proton leak; oxidative phosphorylation impairment and ATP synthesis decrease; iv) induction of fatty liver via inhibition of carnitine palmitoyltransferase I, enhancing nuclear receptor peroxisome proliferator-activated receptor-gamma and acyl-CoA thioesterase 1, and inducing long-chain fatty acid uptake and triglyceride synthesis. VPA administration aggravates liver injury in individuals with metabolic syndromes. Therapeutic drug monitoring, routine serum levels of transaminases, ammonia, and lipid parameters during VPA therapy may thus be beneficial in improving the safety profile or preventing the progression of DILI.



中文翻译:

丙戊酸诱导的肝损伤:分子毒理学机制的洞察

丙戊酸 (VPA) 是一种抗癫痫药物,可导致异质性肝损伤。2-丙基-4-戊烯酸 (Δ 4 VPA) 是 VPA 的一种代谢物,与 VPA 诱导的肝毒性有关。本综述总结了 VPA 引起的肝损伤的发病机制。VPA 主要通过 i) 释放 Δ 4来诱导肝损伤VPA 代谢物;ii) 谷胱甘肽储存量和抗氧化剂减少,导致氧化应激;iii) 抑制脂肪酸 β-氧化,诱导线粒体 DNA 耗竭和高甲基化;质子泄漏减少;氧化磷酸化损伤和 ATP 合成减少;iv)通过抑制肉碱棕榈酰转移酶I、增强核受体过氧化物酶体增殖物激活受体-γ和酰基辅酶A硫酯酶1以及诱导长链脂肪酸摄取和甘油三酯合成来诱导脂肪肝。VPA 给药会加重代谢综合征患者的肝损伤。因此,VPA 治疗期间的治疗药物监测、常规血清转氨酶水平、氨和脂质参数可能有助于提高安全性或预防 DILI 的进展。

更新日期:2022-09-01
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