Mechanisms of endotoxin-induced haem oxygenase mRNA accumulation in mouse liver: synergism by glutathione depletion and protection by N-acetylcysteine.
In in vitro systems haem oxygenase-1 (HO-1) mRNA increases after exposure to agents causing oxidative stress. We lowered cellular antioxidant defence systems in vivo by giving mice increasing doses (0.15 g/kg-1.6 g/kg) of DL-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis. Maximum glutathione depletion (80%) coincided with maximum hepatic HO-1 mRNA accumulation (about 20 times), whereas with 50% depletion, accumulation was only doubled. It has been suggested that reactive oxygen and nitrogen intermediates are involved in hepatic toxicity of endotoxin (lipopolysaccharide, LPS); LPS even at low doses [0.1 mg/kg, intraperitoneally (i.p.)] induces HO-1 mRNA about 25-fold after 1 h. Hepatic glutathione depletion (respectively 40% and 80%) after a low (0.3 g/kg) or a high (1.6 g/kg) BSO dose, resulted in potentiation of the HO-1 mRNA accumulation induced by LPS (0.1 mg/kg, i.p.). In the absence of BSO, N-acetylcysteine (NAC) (1 g/kg orally) reduced LPS-induced HO-1 mRNA accumulation to one fourth. Under the same experimental conditions S-adenosylmethionine (SAM) was not effective. NAC also reduced HO-1 mRNA accumulation when administered to mice in which glutathione was depleted and its synthesis blocked by BSO (1.6 g/kg). Thus reactive oxygen intermediates are likely mediators of LPS-induced HO-1 mRNA accumulation, and glutathione content appears to be one of the factors regulating this accumulation in the liver. Our findings are compatible with the theory that HO-1 induction might have a protective function in vivo when defence mechanisms against oxidants are challenged.
Rizzardini
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Carelli
M
M
Cabello Porras
M R
MR
Cantoni
L
L
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D019328:Buthionine Sulfoximine; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000494:pharmacology
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D012436:S-Adenosylmethionine; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione; D000111:Acetylcysteine