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Redox state alteration modulates astrocyte glucuronidation.

T Heurtaux·A Benani·A Bianchi·A Moindrot·D Gradinaru·J Magdalou·P Netter·A Minn
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Abstract

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 microM) 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.

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AnimalsApoptosisAstrocytesBase SequenceCell SurvivalCells, CulturedCricetinaeFemaleGlucuronatesGlucuronosyltransferaseGlutathioneHydrogen PeroxideInflammationMaleOxidation-ReductionPromoter Regions, GeneticProtein IsoformsRNA, MessengerRatsRats, WistarReactive Oxygen SpeciesVitamin K 3Journal Article

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T Heurtaux, A Benani, A Bianchi, A Moindrot, D Gradinaru, J Magdalou, P Netter, A Minn. 2004-10-01. Redox state alteration modulates astrocyte glucuronidation.. https://doi.org/10.1016/j.freeradbiomed.2004.06.020

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