title: Induction of UGT1A6 isoform by inflammatory conditions in rat astrocytes.
abstract: Alteration of drug metabolism under diseased conditions is of clinical importance. We have investigated the effects of inflammatory conditions on phase II drug-metabolizing enzyme activity in rat cultured astrocytes. Lipopolysaccharide (LPS) treatment was used to promote inflammatory conditions. Thus, we reported that LPS initiates an inflammatory response, which is mediated by pro-inflammatory mediators and free radical generation. An increase in astrocyte glucuronidation activity was observed after a 48-h LPS treatment. This increase in glucuronidation activity was associated with an up-regulation of the UGT1A6 isoform mRNA level as shown by RT-PCR and gene reporter assay. Moreover, this endotoxin-induced increase in UGT1A6 expression level was blocked by actinomycin D and cycloheximide, indicating the requirement for RNA and protein synthesis. The UGT1A6 expression enhancement could be prevented by anti-inflammatory drugs (dexamethasone and NS398) or nitric oxide synthase inhibitors (L-NAME and L-NMMA). Moreover, gel shift assay revealed increased activator protein-1 (AP-1) binding activity after LPS treatment. We propose, based on the data presented, that the action of LPS to induce UGT1A6 isoform up-regulation may be mediated by pro-inflammatory mediator accumulation, and AP-1 binding activity increase.
authors.affiliation: Unité Mixte de Recherche CNRS - Université Henri Poincaré Nancy 1, No 7561, Laboratoire de Pharmacologie, Faculté de Médecine, BP 184, 54505 Vandoeuvre-lès-Nancy Cedex, France.
authors.forename: T
authors.initials: T
authors.lastname: Heurtaux
authors.forename: A
authors.initials: A
authors.lastname: Benani
authors.forename: D
authors.initials: D
authors.lastname: Moulin
authors.forename: N
authors.initials: N
authors.lastname: Muller
authors.forename: P
authors.initials: P
authors.lastname: Netter
authors.forename: A
authors.initials: A
authors.lastname: Minn
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D015152:Blotting, Northern; D002470:Cell Survival / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009573:Nitrites / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D014453:Glucuronosyltransferase; C107611:UDP-glucuronosyltransferase, UGT1A7; D015232:Dinoprostone