Endotoxin from various gram-negative bacteria has differential effects on function of hepatic cytochrome P450 and drug transporters

Abstract

The differential effects of endotoxin derived from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli on hepatic cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activity and on the expression of hepatic CYP3A2, CYP2C11, P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) was investigated in rats. Endotoxin from all three different pathogens significantly decreased the systemic clearance of antipyrine, reflecting reduced hepatic drug-metabolizing enzyme activity 24 h after intravenous injection (0.5 mg/kg). The degree of the decreased systemic clearance by P. aeruginosa endotoxin was smaller than that by both K. pneumoniae and E. coli endotoxin. Western blot analysis revealed that the down-regulation of CYP3A2 by K. pneumoniae and E. coli endotoxin was greater than that by P. aeruginosa endotoxin. However, the down-regulation of CYP2C11 by all three different endotoxin was almost the same. Both K. pneumoniae and P. aeruginosa endotoxin significantly down-regulated P-glycoprotein, but did not down-regulate Mrp2. E. coli endotoxin had no effect on the expression of either P-glycoprotein or Mrp2, probably due to the low dose used. The down-regulation of CYP3A2 by endotoxin was parallel to the decreased systemic clearance of antipyrine. These results suggest that endotoxin has a differential effect on the hepatic CYP-mediated drug-metabolizing enzyme activity, and on the protein levels of hepatic CYP3A2 and P-glycoprotein, probably due to bacterial source-differences in the production of some proinflammatory mediators. Endotoxin appears to regulate coordinately CYP3A2, CYP2C11 and P-glycoprotein, but not Mrp2.