Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction
Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction
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DOI：
10.1002/jbt.10043
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发表时间：
2002-01-01
影响因子：
3.6
通讯作者：
Manautou, JE
中科院分区：
文献类型：
--
作者：
Chen, C;Hennig, GE;Manautou, JE
用过氧化体增殖剂氯贝特(CFB)预处理的小鼠对对乙酰氨基酚(APAP)诱导的肝毒性具有高度抵抗力。本研究的目的是探讨体外循环预处理后肝脏过氧化氢酶活性的升高是否在这种肝脏保护中起作用。不可逆的抑制剂3-氨基-1，2，4-三氮唑(3-AT)用于调节过氧化氢酶的活性。3-AT(100或500 mg/kg)可显著抑制CFB(500 mg/kg，ip，连续10天)小鼠肝脏过氧化氢酶的活性。此外，较低剂量的3-AT(100 mg/kg)对非毒性剂量的APAP代谢产物的胆汁和尿液排泄的影响很小，表明该剂量的3-AT不调节APAP的代谢。APAP(800 mg/kg，P.O.)对玉米油预处理小鼠的致死率有显著影响。3-AT(100 mg/kg，i.p.)如预期的那样，在APAR之前给予1it，CFB预处理对APAP所致的肝毒性具有完全的保护作用。然而，同样的3-AT处理并没有取消CFB处理的小鼠的肝脏保护作用，尽管显著抑制了肝脏过氧化氢酶的活性。综上所述，这些结果表明，暴露于CFB的小鼠体内过氧化氢酶活性的升高似乎并不参与肝脏保护，这表明其他细胞防御机制也参与其中。(C)2002年威利期刊公司。
Mice pretreated with the peroxisome proliferator clofibrate (CFB) are highly resistant to acetaminophen (APAP)-induced hepatotoxicity. The objective of the present study was to investigate whether the increase in hepatic catalase activity following CFB pretreatment plays a role in this hepatoprotection. An irreversible inhibitor, 3-amino-1,2,4-triazole (3-AT), was used to modulate catalase activity. Hepatic catalase activity in mice pretreated with CFB (500 mg/kg, i.p., for 10 days) was significantly inhibited by 3-AT (100 or 500 mg/kg, i.p.). In addition, the lower dose of 3-AT (100 mg/kg) had minimal effect on biliary and urinary excretion of APAP metabolites generated from a nontoxic dose, suggesting that APAP metabolism was not modulated by this dose of 3-AT. The mortality rate of corn-oil-pretreated mice challenged with APAP (800 mg/kg, p.o.) was significantly increased by 3-AT (100 mg/kg, i.p.) given 1 It before APAR As expected, CFB pretreatment conferred full protection against APAP-induced hepatotoxicity. The same 3-AT treatment, however, did not abolish hepatoprotection in CFB-pretreated mice, despite the marked inhibition of hepatic catalase activity. In conclusion, these results indicate that elevated catalase activity in mice exposed to CFB does not appear to mediate the hepatoprotection, suggesting that other cellular defense mechanisms are involved. (C) 2002 Wiley Periodicals, Inc.