期刊
NEUROPHARMACOLOGY
卷 50, 期 3, 页码 317-328出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2005.09.007
关键词
brain; metabolism; nitric oxides; prostaglandin E-2; UGT1A6; EMSA
Alteration of drug metabolism under diseased conditions is of clinical importance. We have investigated the effects of inflammatory conditions on phase H 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. (c) 2005 Elsevier Ltd. All rights reserved.
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