Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5832411 | International Immunopharmacology | 2015 | 6 Pages |
Abstract
Liver plays a central role in xenobiotics metabolism, thus affecting the in vivo disposition 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 substrate p-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 -â and Cmax of imidaprilat were decreased from 2084.86 ± 340.66 ng · hâ 1 · mLâ 1 and 234.66 ± 68.85 ng · mLâ 1 to 983.87 ± 315.34 ng · hâ 1 · mLâ 1 and 113.1 ± 19.69 ng · mLâ 1 (P < 0.05), respectively. Moreover, AUC0 -â and Cmax of SN-38 were decreased from 8100 ± 918.6 ng · hâ 1 · mLâ 1 and 144.67 ± 20.28 ng · mLâ 1 to 3270 ± 500.5 ng · hâ 1 · mLâ 1 and 56.19 ± 10.38 ng · mLâ 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.
Keywords
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Authors
Chengliang Zhang, Yanjiao Xu, Ping Gao, Jingli Lu, Xiping Li, Dong Liu,