对乙酰氨基酚诱导的大鼠胆酸盐蓄积性肝损伤机制研究（英文）

Acetaminophen-induced hepatotoxicity in rats is correlated with the accumulation of bile acids: an underlying mechanism

通过测定血浆和肝组织中胆酸盐(BAs)含量的变化及肝组织中转运体表达水平的变化,初步探究对乙酰氨基酚(APAP)致大鼠的肝损伤的机制。SD大鼠42只,随机分为6-h对照组、APAP 6-h组、12-h对照组、APAP 12-h组、24-h对照组和APAP 24-h组。运用LC-MS/MS测定血浆和肝组织中BAs含量;Western blotting评价Bsep、Mrp2、Mrp4、Ntcp和Oatp2表达水平。APAP 6-h组,与6-h对照组相比,血浆和肝组织中BAs含量及肝组织中转运蛋白的表达水平无显著差异。APAP 12-h组,与12-h对照组比较,血浆中BAs含量明显降低(P<0.05),肝组织中BAs含量明显升高(P<0.05);Bsep和Mrp2表达水平显著降低(P<0.05)。APAP 24-h组,与24-h对照组比较,血浆和肝组织中BAs含量均明显升高(P<0.05);Mrp4和Oatp2表达水平显着降低(P<0.05)。APAP诱导的大鼠肝损伤机制可能与其在不同时间抑制Bsep,Mrp2,Mrp4和Oatp2表达水平导致BAs蓄积有关。

In the present study, we aimed to investigate the underlying mechanism of acetaminophen（APAP）-induced hepatotoxicity by measuring the expression levels of liver transporters and concentrations of bile acids（BAs） in rat plasma and liver. SD rats（42） were randomly assigned into six groups, including 6-h control group, APAP 6-h group, 12-h control group, APAP 12-h group, 24-h control group and APAP 24-h group. The estimation study of BAs in plasma and liver was performed on LC-MS/MS. The levels of bile salt export pump（Bsep）, multidrug resistant protein 2（Mrp2）, multidrug resistant protein 4（Mrp4）, Na＋/taurocholate cotransporting polypeptide（Ntcp） and organic anion transporting polypeptide 2（Oatp2） in the liver were analyzed by Western blotting analysis. Compared with the corresponding control groups, no difference was found in the BA levels and the expressions of BA transporters in the plasma and liver after 6 h of APAP administration. While BA levels were significantly decreased in the plasma and increased in the liver after 12 h of APAP administration（P0.05）; and the expressions of Bsep and Mrp2 were significantly reduced（P0.05）. After 24 h of APAP administration, BA levels were both greatly increased in the plasma and liver（P0.05）; and the expressions of Mrp4 and Oatp2 were significantly decreased（P0.05）. In response to over-dose APAP, Bsep, Mrp2, Mrp4 and Oatp2 levels were reduced at different time points, causing the accumulation of BAs, and such accumulation may ultimately lead to the severe liver injury, which could be an underlying mechanism of the APAP-induced hepatotoxicity.