Induction of UGT1A6 isoform by inflammatory conditions in rat astrocytes.
Neuropharmacology
; 50(3): 317-28, 2006 Mar.
Article
em En
| MEDLINE
| ID: mdl-16274708
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.
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Base de dados:
MEDLINE
Assunto principal:
Indução Enzimática
/
Lipopolissacarídeos
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Astrócitos
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Glucuronosiltransferase
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Inflamação
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article