Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain.
In mammalian systems, the heme oxygenase (HO) isozymes HO-1 (HSP32) and HO-2 oxidatively cleave the heme molecule to produce bile pigments and carbon monoxide. Although HO-1 is inducible by various chemicals in systemic organs and cell culture systems, this communication reports for the first time the induction of this stress protein and its transcript by a chemical in the brain. In addition, this study demonstrates expression of HO-1 in select populations of cells in the brain in response to GSH depletion. Specifically, treatment of adult rats with diethyl maleate (DEM; 4.7 mmol/kg) caused a pronounced decrease in brain GSH content within 1 h. GSH levels remained significantly depressed for at least 24 h postinjection. Northern blot analysis of brain poly(A)+ mRNA following DEM treatment revealed on the average a sixfold increase in the 1.8-kb HO-1 mRNA level compared with that of controls; concomitant with this change was a decrease in GSH levels. Total brain HO activity was not significantly altered along with the increase in HO-1 mRNA level. The increase in transcription of HO-1 was a direct response to GSH depletion, as judged by the observation that treatment of neonatal rats with L-buthionine-(S,R)-sulfoximine (BSO) (3 mmol/kg, twice daily, for 2 days), a selective inhibitor of GSH synthesis, caused a marked depression in total brain GSH level and a concomitant increase in brain 1.8-kb HO-1 mRNA content. The magnitude of the increase was up to approximately 11.5-fold that of the control level, as evidenced by northern blot analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Ewing
J F
JF
Department of Biophysics, University of Rochester School of Medicine, New York 14642.
Maines
M D
MD
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats
D008298:Maleates; D012333:RNA, Messenger; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D006419:Heme Oxygenase (Decyclizing); C014476:diethyl maleate; D005978:Glutathione