Redox state alteration modulates astrocyte glucuronidation

We have investigated the effects of mild oxidative conditions on drug-metabolizing enzyme activity in rat cultured astrocytes. These experimental conditions promoting an oxidative environment were obtained by short exposure to a low concentration of menadione (5 μM) for a short duration (15 min). Th...

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Bibliographic Details
Published in:Free radical biology & medicine 2004-10, Vol.37 (7), p.1051-1063
Main Authors: Heurtaux, T., Benani, A., Bianchi, A., Moindrot, A., Gradinaru, D., Magdalou, J., Netter, P., Minn, A.
Format: Article
Language:English
Subjects:
Aging
Animals
Apoptosis - drug effects
Astrocytes - cytology
Astrocytes - drug effects
Astrocytes - metabolism
Base Sequence
Brain
Cell Survival - drug effects
Cells, Cultured
Cricetinae
Female
Free radicals
Glucuronates - metabolism
Glucuronosyltransferase - chemistry
Glucuronosyltransferase - metabolism
Glutathione - metabolism
Hydrogen Peroxide - pharmacology
Inflammation - metabolism
Male
Metabolism
Oxidation-Reduction - drug effects
Oxidative stress
Promoter Regions, Genetic
Protein Isoforms - chemistry
Protein Isoforms - metabolism
Protein oxidation
Rats
Rats, Wistar
Reactive Oxygen Species - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
UGT1A6
Vitamin K 3 - pharmacology
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Summary:We have investigated the effects of mild oxidative conditions on drug-metabolizing enzyme activity in rat cultured astrocytes. These experimental conditions promoting an oxidative environment were obtained by short exposure to a low concentration of menadione (5 μM) for a short duration (15 min). This resulted in the rapid and transient production of reactive oxygen species (+130%), associated with a decrease in GSH cellular content (−24%), and an increase in total protein oxidation (+26%), but promoted neither PGE 2 nor NO production. This treatment induced a rapid and persistent decrease in astrocyte glucuronidation activities, which was totally prevented by N-acetyl- l-cysteine. These oxidative conditions also affected the specific UGT1A6 activity measured in transfected V79-1A6 cells. Finally, the subsequent recovery of astrocyte glucuronidation activity may result from upregulation of UGT1A6 expression (+62%) as shown by RT-PCR and gene reporter assay. These results show that the catalytic properties and expression of cerebral UGT1A6 are highly sensitive to the redox environment. The protective effect of N-acetyl- l-cysteine suggests both a direct action of reactive oxygen species on the protein and a more delayed action on the transcriptional regulation of UGT1A6. These results suggest that cerebral metabolism can be altered by physiological or pathological redox modifications.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2004.06.020