Cytochrome P450 induction by phenobarbital exacerbates warm hepatic ischemia-reperfusion injury in rat livers

Abstract

Recent studies have shown that cytochrome P450 inhibitors reduce oxidative stress and injury to the liver following warm ischemia-reperfusion (IR). The aim here was to test the effect of P450 induction by phenobarbital on the IR injury in rat livers. Rats were pre-treated with saline or phenobarbital and subjected to IR or sham operation. IR significantly increased the plasma alanine aminotransferase concentrations. Phenobarbital further exacerbated the injury by an additional 50% increase in the alanine aminotransferase levels. Phenobarbital also caused an ∼40% increase in the total P450 content of the liver, which was also associated with a 75% increase in the reactive oxygen species (ROS) generation in the IR group. There was a strong correlation between the microsomal ROS generation and total P450 content, CYP3A2 activity or CYP2B1 activity. It is concluded that the induction of P450 by phenobarbital significantly increases hepatic production of ROS, leading to significantly higher hepatic IR injury.

Keywords::

• Hepatic ischemia-reperfusion injury
• reactive oxygen species
• cytochrome P450
• enzyme induction
• phenobarbital
• microsomes

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This paper was first published online on Early Online on 12 February 2010.