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Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction
Author(s) -
Chen Chuan,
Hennig Gayle E.,
Whiteley Herbert E.,
Manautou José E.
Publication year - 2002
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.10043
Subject(s) - hepatoprotection , catalase , chemistry , clofibrate , acetaminophen , pharmacology , peroxisome proliferator , peroxisome , excretion , biochemistry , enzyme , medicine , glutathione , receptor
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 h before APAP. 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. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:227–234, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10043