Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice.
This study examined the effects and possible mechanisms of rifampin against acetaminophen-induced hepatotoxicity in mice. Rifampin significantly enhanced the biotransformation of acetaminophen, evidenced by the increase in p-aminophenol formation in rifampin-treated microsomes and the increase in plasma clearance rate of acetaminophen. Pretreatment with rifampin significantly decreased serum alanine transaminase (ALT) activities, aspartate transaminase (AST) activities and prevented severe liver necrosis following acetaminophen overdose. The contents and activities of microsomal drug-metabolizing enzyme were less affected in rifampin-pretreated mice in comparison to the animals treated with acetaminophen alone. Rifampin was capable of increasing glutathione (GSH) level and GSH reductase activity and reducing GSH depletion and the decrease in GSH reductase activity by acetaminophen in mice. In addition, it was found that the microsomal Ca(2+)-ATPase activity was not directly related to acetaminophen toxic species generated in the P450 enzyme system in vitro. These findings suggest that rifampin has species-specific effects on the liver against acetaminophen-induced hepatotoxicity in mice, which increase the level of GSH by promoting GSH regeneration.
Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi 530021, PR China.
Min
M
He
Shijun
S
Zhang
Yang
Y
Jiao
Xing
X
Lin
Jianchun
J
Huang
Chunxia
C
Chen
Zhaoni
Z
Chen
Renbin
R
Huang
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D012293:Rifampin / Q000494:pharmacology*
D000082:Acetaminophen; D005980:Glutathione Reductase; D005978:Glutathione; D012293:Rifampin