Our previous study showed that silymarin, a mixture of flavonolignans extracted from seeds of milk thistle, modulated hepatic transsulfuration reactions, leading to an increase in glutathione (GSH) synthesis. To investigate its pharmacological significance, we determined the effect of silymarin on acetaminophen (APAP)-induced liver injury. Silymarin administration to mice prevented the induction of APAP-hepatotoxicity as measured by changes in plasma enzyme activities, hepatic lipid peroxidation and formation of nitrotyrosine protein-adducts. Depletion of hepatic GSH was inhibited significantly. Plasma APAP, APAP-glucuronide or APAP-sulfate level was not changed, but APAP-GSH, APAP-cysteine and APAP-N-acetylcysteine levels were elevated. Silymarin treatment did not induce proteins or activities of Cyp2e1, Cyp1a2, and Cyp3a11, the major cytochrome P450 subtypes responsible for the metabolic activation of APAP to a reactive metabolite, N-acetyl-p-benzoquinoneimine. The results suggest that the hepatoprotective effect of silymarin is associated with an increase in the metabolic disposition of N-acetyl-p-benzoquinoneimine via up-regulation of the GSH conjugation capacity.

我们以前的研究表明，水飞蓟素（一种从水飞蓟种子中提取的黄酮木聚糖的混合物）调节肝脏的转硫反应，从而导致谷胱甘肽（GSH）合成的增加。为了研究其药理学意义，我们确定了水飞蓟素对乙酰氨基酚（APAP）诱导的肝损伤的作用。通过对血浆酶活性，肝脂质过氧化作用和硝基酪氨酸蛋白加合物的形成进行测量，对小鼠施用水飞蓟素可防止诱导APAP肝毒性。肝谷胱甘肽的消耗被显着抑制。血浆APAP，APAP-葡萄糖醛酸或APAP-硫酸盐水平未改变，但APAP-GSH，APAP-半胱氨酸和APAP- N-乙酰半胱氨酸水平升高。水飞蓟素处理不会诱导Cyp2e1，Cyp1a2和Cyp3a11的蛋白质或活性，Cyp2e1，Cyp1a2和Cyp3a11是负责APAP代谢活化为反应性代谢物N-乙酰基-p-苯并醌亚胺的主要细胞色素P450亚型。结果表明，水飞蓟素的肝保护作用与通过上调GSH结合能力而增加N-乙酰基-对-苯并醌亚胺的代谢作用有关。