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 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.
Heurtaux
T
T
Unité Mixte de Recherche CNRS, Université Henri Poincaré Nancy 1, No. 7561, Laboratoire de Pharmacologie, Faculté de Médecine, BP 184, 54505 Vandoeuvre-lès-Nancy Cedex, France.
Benani
A
A
Bianchi
A
A
Moindrot
A
A
Gradinaru
D
D
Magdalou
J
J
Netter
P
P
Minn
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology
D005965:Glucuronates; D020033:Protein Isoforms; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D014453:Glucuronosyltransferase; D005978:Glutathione