Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-8-24
pubmed:abstractText
Carboxylesterases constitute a class of enzymes that play important roles in the hydrolytic metabolism of drugs and other xenobiotics. Patients with liver conditions such as cirrhosis show increased secretion of proinflammatory cytokines [e.g., interleukin-6 (IL-6)] and decreased capacity of hydrolysis. In this study, we provide a molecular explanation linking cytokine secretion directly to the decreased capacity of hydrolytic biotransformation. In both primary hepatocytes and HepG2 cells, treatment with IL-6 decreased the expression of human carboxyl-esterases HCE1 and HCE2 by as much as 60%. The decreased expression occurred at both mRNA and protein levels, and it was confirmed by enzymatic assay. In cotransfection experiments, both HCE1 and HCE2 promoters were significantly repressed, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting that transrepression is responsible for the suppressed expression. In addition, pretreatment with IL-6 altered the cellular responsiveness in an opposite manner of overexpression of HCE1 and HCE2 toward various ester therapeutic agents (e.g., clopidogrel). Transfection of HCE1, for example, decreased the cytotoxicity induced by antithrombogenic agent clopidogrel, whereas pretreatment with IL-6 increased the cytotoxicity. Such a reversal was observed with other ester drugs, including anticancer agent irinotecan and anti-influenza agent oseltamivir. The altered cellular responsiveness was observed when drugs were assayed at sub- and low-micromolar concentrations, suggesting that suppressed expression of carboxylesterases by IL-6 has profound pharmacological consequences, particularly with those that are hydrolyzed in an isoform-specific manner.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic, http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents, http://linkedlifedata.com/resource/pubmed/chemical/CES1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CES2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Camptothecin, http://linkedlifedata.com/resource/pubmed/chemical/Carboxylesterase, http://linkedlifedata.com/resource/pubmed/chemical/Carboxylic Ester Hydrolases, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6, http://linkedlifedata.com/resource/pubmed/chemical/Oseltamivir, http://linkedlifedata.com/resource/pubmed/chemical/Platelet Aggregation Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Ticlopidine, http://linkedlifedata.com/resource/pubmed/chemical/clopidogrel, http://linkedlifedata.com/resource/pubmed/chemical/irinotecan
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
72
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
686-94
pubmed:dateRevised
2010-5-20
pubmed:meshHeading
pubmed-meshheading:17537833-Adult, pubmed-meshheading:17537833-Aged, pubmed-meshheading:17537833-Antineoplastic Agents, Phytogenic, pubmed-meshheading:17537833-Antiviral Agents, pubmed-meshheading:17537833-Camptothecin, pubmed-meshheading:17537833-Carboxylesterase, pubmed-meshheading:17537833-Carboxylic Ester Hydrolases, pubmed-meshheading:17537833-Carcinoma, Hepatocellular, pubmed-meshheading:17537833-Cell Line, Tumor, pubmed-meshheading:17537833-Cells, Cultured, pubmed-meshheading:17537833-Dose-Response Relationship, Drug, pubmed-meshheading:17537833-Female, pubmed-meshheading:17537833-Hepatocytes, pubmed-meshheading:17537833-Humans, pubmed-meshheading:17537833-Interleukin-6, pubmed-meshheading:17537833-Liver Neoplasms, pubmed-meshheading:17537833-Male, pubmed-meshheading:17537833-Middle Aged, pubmed-meshheading:17537833-Oseltamivir, pubmed-meshheading:17537833-Platelet Aggregation Inhibitors, pubmed-meshheading:17537833-RNA, Messenger, pubmed-meshheading:17537833-Ticlopidine
pubmed:year
2007
pubmed:articleTitle
Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2.
pubmed:affiliation
Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, N.I.H., Extramural