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首页> 外文期刊>Pharmacology and Toxicology: An International Journal >Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.
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Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.

机译：丙戊酸在异源生物诱导的肝毒性中的触发功能的证据。

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摘要

The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.
机译：研究了抗癫痫药丙戊酸（2-正丙基戊酸）对肝细胞应对外源性氧化应激的影响。新鲜暴露的大鼠肝细胞暴露于治疗浓度的丙戊酸（0.25-1.0 mmol / l），其抗药性低于对照组，这是通过用无毒剂量的烯丙醇（2-丙氨酸）攻击细胞后产生的明显细胞毒性反应所证明的。 -1-ol）。单独的丙戊酸即使在十倍高的浓度（10 mmol / l）下对肝细胞也没有毒性，表明细胞损伤不仅仅是单纯的累加作用。与丙戊醇和烯丙醇一起孵育会引起肝细胞谷胱甘肽的不可逆消耗，这与单独的烯丙醇会引起短暂的损失相反。用丙戊酸加烯丙醇处理的肝细胞受到谷胱甘肽的前体N-乙酰半胱氨酸的保护。这些发现表明丙戊酸影响肝细胞防御机制，并暗示肝细胞易患氧化应激可能在癫痫患者的丙戊酸致命的肝毒性中起作用。

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