title: Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-κB pathway.
abstract: Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-κB inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-κB pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, 140 Han Zhong Rd., Nanjing, Jiangsu 210029, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Mao
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Luan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Gui
authors.forename: Xuemin
authors.initials: X
authors.lastname: Feng
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Jianping
authors.initials: J
authors.lastname: Shen
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077144:Clopidogrel; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D000077146:Irinotecan; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D000077146:Irinotecan; D000077144:Clopidogrel; D048051:p38 Mitogen-Activated Protein Kinases; D002265:Carboxylic Ester Hydrolases; C545375:carboxylesterase 1, mouse; D043182:Carboxylesterase; C500145:Ces2c protein, mouse; D013988:Ticlopidine; D002166:Camptothecin