Redox state alteration modulates astrocyte glucuronidation

• 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
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2004.06.020

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.