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Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice
Authors:Min He  Shijun Zhang  Yang Jiao  Xing LinJianchun Huang  Chunxia ChenZhaoni Chen  Renbin Huang
Affiliation:Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi 530021, PR China
Abstract: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 Ca2+-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.
Keywords:Rifampin   Acetaminophen hepatotoxicity   Mice   Glutathione   Glutathione reductase   Ca2+-ATPase
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