Level of haem oxygenase does not obligatorily reflect the sensitivity of PC12 cells to an oxidative shock induced by glutathione depletion.
In order to investigate the function of haem oxygenase in neuronal cell death or survival, we have determined in PC12 cells whether induction of haem oxygenase mRNA and protein or inhibition of haem oxygenase activity may be able to modulate the cell response to an oxidative stress. Inhibition of glutathione biosynthesis by buthionine sulfoximine (BSO) has indeed been demonstrated, in this cell line, to decrease the intracellular content of glutathione and to trigger a gradual and programmed cell death. Inhibition of haem oxygenase by zinc protoporphyrin IX, a potent inhibitor of this enzyme, or by a recently described peptidic inhibitor, induced a significant decrease in the toxicity of BSO. This protective action was not due to an alteration in the metabolism of glutathione and was still observed when the protecting agent was added several hours after BSO treatment. Induction of haem oxygenase-1 mRNA and protein by either haemin or pyrrolidine dithiocarbamate was associated with no protection or a significant reduction in the toxicity of BSO respectively. Our results indicate that induction of haem oxygenase-1 is not obligatorily associated with an improved resistance towards oxidative stress and suggest that a byproduct of haem degradation may also become detrimental.
Leon
Albertine
A
Centre National de la Recherche Scientifique Unité mixte de Recherche, Université de Caen, Caen, France.
Le Foll
Isabelle
I
Charriault-Marlangue
Christiane
C
Leprince
Jérome
J
Vaudry
Hubert
H
Gabriel
Cécilia
C
Duval
Dominique
D
D000818:Animals; D001663:Bilirubin / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006162:Guanylate Cyclase; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010069:Oxadiazoles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D011759:Pyrrolidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D013859:Thiocarbamates / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D011759:Pyrrolidines; D011810:Quinoxalines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D019328:Buthionine Sulfoximine; D006427:Hemin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005978:Glutathione; D001663:Bilirubin