Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats.
Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats.
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DOI：
10.1016/j.intimp.2014.12.003
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发表时间：
2015-02
影响因子：
5.6
通讯作者：
Chengliang Zhang;Yanjiao Xu;P. Gao;Jingli Lu;Xiping Li;Dong Liu
中科院分区：
文献类型：
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作者：
Chengliang Zhang;Yanjiao Xu;P. Gao;Jingli Lu;Xiping Li;Dong Liu
肝脏在外源性药物的代谢中起着重要作用，从而影响药物在体内的分布和疗效。羧酸酯酶（CES），主要亚型为CES 1和CES 2，在酯型前药的代谢中非常重要。然而，免疫性肝损伤对CES活性的影响仍不清楚。在本研究中，我们证明了脂多糖（LPS）的治疗抑制了CES 1和CES 2的活性。用大鼠肝微粒体酶水解其共同底物乙酸对硝基苯酯（PNPA）的方法，初步评价了CES 1和CES 2活性的降低。RT-PCR结果显示，模型组大鼠脑组织中CES 1、CES 2（AB 010635）和CES 2（AY 034877）的mRNA水平均显著低于正常对照组（P< 0.05）。Western blot结果显示，CES 1和CES 2蛋白表达降低（P< 0.05）。为了进一步阐明LPS对CESs代谢活性的影响，分别使用咪达普利和伊立替康（CPT-11）作为CES 1和CES 2的特异性底物，在大鼠中进行药代动力学研究。LPS处理后，咪唑普利拉的AUC 0-∞和Cmax分别由2084.86 ± 340.66 ng · h-1· mL-1和234.66 ± 68.85 ng · mL-1降至983.87 ± 315.34 ng · h-1· mL-1和113.1 ± 19.69 ng · mL-1（P< 0.05）。SN-38的AUC 0-∞和Cmax分别从8100 ± 918.6 ng · h− 1· mL− 1和144.67 ± 20.28 ng · mL− 1降至3270 ± 500.5 ng · h− 1· mL− 1和56.19 ± 10.38 ng · mL− 1（P< 0.05）。综上所述，免疫性肝损伤显著减弱了CES 1和CES 2的表达和代谢活性，这可能与炎症状态下细胞因子的调节作用有关。
Liver plays a central role in xenobiotics metabolism, thus affecting thein vivodisposition and therapeutic effects of drugs. Carboxylesterases (CESs), with the main isoforms CES1 and CES2, are important in the metabolism of ester-type prodrugs. However, influences of immunological liver injury on the activity of CES remain undefined. In the present study, we demonstrated treatment with lipopolysaccharide (LPS) suppressed the activities of CES1 and CES2. The decreased activities of CES1 and CES2 were preliminarily assessed by the hydrolysis assay for their common substratep-nitrophenyl acetate (PNPA) with rat hepatic microsomal enzyme. Subsequently, RT-PCR results showed that the levels of CES1 mRNA and mRNA of CES2 (AB010635) and CES2 (AY034877) in the model group were significantly lower than those of the normal control group (P< 0.05). Western blot results showed that the expressions of CES1 and CES2 proteins were decreased (P< 0.05). To further clarify the effects of LPS on the metabolic activities of CESs, pharmacokinetic studies were performed in rats by utilizing imidapril and irinotecan (CPT-11) as the specific substrates for CES1 and CES2, respectively. After treatment with LPS, AUC0 -∞and Cmaxof imidaprilat were decreased from 2084.86 ± 340.66 ng · h− 1· mL− 1and 234.66 ± 68.85 ng · mL− 1to 983.87 ± 315.34 ng · h− 1· mL− 1and 113.1 ± 19.69 ng · mL− 1(P< 0.05), respectively. Moreover, AUC0 -∞and Cmaxof SN-38 were decreased from 8100 ± 918.6 ng · h− 1· mL− 1and 144.67 ± 20.28 ng · mL− 1to 3270 ± 500.5 ng · h− 1· mL− 1and 56.19 ± 10.38 ng · mL− 1(P< 0.05), respectively. In summary, immunological liver injury remarkably attenuated the expressions and metabolic activities of CES1 and CES2, which may be associated with the regulatory effects of cytokines under inflammation.