MECHANISMS OF ENDOTOXIN-INDUCED HEME OXYGENASE MESSENGER-RNA ACCUMULATION IN MOUSE-LIVER - SYNERGISM BY GLUTATHIONE DEPLETION AND PROTECTION BY N-ACETYLCYSTEINE

被引:95
作者
RIZZARDINI, M [1 ]
CARELLI, M [1 ]
PORRAS, MRC [1 ]
CANTONI, L [1 ]
机构
[1] IST RIC FARMACOL MARIO NEGRI, I-20157 MILAN, ITALY
关键词
D O I
10.1042/bj3040477
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 potentiationof 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.
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页码:477 / 483
页数:7
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