title: Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats.
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-∞ and Cmax of imidaprilat were decreased from 2084.86±340.66ng·h(-1)·mL(-1) and 234.66±68.85ng·mL(-1) to 983.87±315.34ng·h(-1)·mL(-1) and 113.1±19.69ng·mL(-1) (P<0.05), respectively. Moreover, AUC0-∞ and Cmax of SN-38 were decreased from 8100±918.6ng·h(-1)·mL(-1) and 144.67±20.28ng·mL(-1) to 3270±500.5ng·h(-1)·mL(-1) and 56.19±10.38ng·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.
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Wuhan Children's Hospital, Wuhan, 430030,China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xiping
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: ld2069@outlook.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D048289:Imidazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077146:Irinotecan; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
chemical_list: D048289:Imidazolidines; D008070:Lipopolysaccharides; D011355:Prodrugs; D000077146:Irinotecan; C065166:imidapril; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin
keywords: Carboxylesterases; Imidapril; Immunological liver injury; Irinotecan