Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Molecules. 2022 Dec 13;27(24):8855. doi: 10.3390/molecules27248855.
Previous studies have shown that silymarin protects against various types of drug-induced liver injury, but whether the protective mechanism of silymarin against acetaminophen-induced liver injury is related to the CYP2E1 enzyme remains unclear. In this study, we investigated the effect of silymarin on the activity and expression of CYP2E1 in vitro and in vivo. The results of in vitro studies showed that silymarin not only inhibited the activity of CYP2E1 in human and rat liver microsomes but also reduced the expression of CYP2E1 in HepG2 cells. In vivo studies showed that silymarin pretreatment significantly reduced the conversion of chlorzoxazone to its metabolite 6-OH-CLX and significantly increased the t, area under the curve (AUC) and mean residence time (MRT) of chlorzoxazone. In addition, silymarin pretreatment significantly inhibited the upregulation of Cyp2e1 expression, reduced the production of 3-cysteinylacetaminophen trifluoroacetic acid salt (APAP-CYS), and restored the liver glutathione level. The results of our study show that silymarin plays an important protective role in the early stage of acetaminophen-induced acute liver injury by reducing the activity and expression of CYP2E1, reducing the generation of toxic metabolites, and alleviating liver injury.
先前的研究表明水飞蓟素可预防各种类型的药物性肝损伤，但水飞蓟素对乙酰氨基酚诱导的肝损伤的保护机制是否与 CYP2E1 酶有关尚不清楚。在这项研究中，我们研究了水飞蓟素在体外和体内对 CYP2E1 活性和表达的影响。体外研究结果表明，水飞蓟素不仅抑制人肝微粒体和大鼠肝微粒体中 CYP2E1 的活性，还降低 HepG2 细胞中 CYP2E1 的表达。体内研究表明，水飞蓟素预处理可显著减少氯唑沙宗转化为其代谢产物 6-OH-CLX，并显著增加氯唑沙宗的 t 1/2、曲线下面积（AUC）和平均驻留时间（MRT）。此外，水飞蓟素预处理可显著抑制 Cyp2e1 表达上调，减少 3-半胱氨酰乙酰氨基酚三氟乙酸盐（APAP-CYS）的产生，并恢复肝脏谷胱甘肽水平。我们的研究结果表明，水飞蓟素通过降低 CYP2E1 的活性和表达、减少有毒代谢物的生成以及减轻肝损伤，在乙酰氨基酚诱导的急性肝损伤早期发挥重要的保护作用。
