Induction of UGT1A6 isoform by inflammatory conditions in rat astrocytes

Neuropharmacology. 2006 Mar;50(3):317-28. doi: 10.1016/j.neuropharm.2005.09.007. Epub 2005 Nov 7.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects*
  • Astrocytes / enzymology
  • Blotting, Northern
  • Cell Survival / drug effects
  • Dinoprostone / metabolism
  • Drug Interactions
  • Enzyme Induction / drug effects*
  • Enzyme Induction / physiology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glucuronosyltransferase / biosynthesis*
  • Glucuronosyltransferase / metabolism
  • Green Fluorescent Proteins / biosynthesis
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mutagenesis / physiology
  • Mutation
  • Nitrites / metabolism
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / physiology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Time Factors
  • Transfection / methods
  • Tumor Necrosis Factor-alpha / pharmacology


  • Enzyme Inhibitors
  • Interleukin-1
  • Lipopolysaccharides
  • Nitrites
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Green Fluorescent Proteins
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase, UGT1A7
  • Dinoprostone