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

Eur J Pharmacol. 2005 Mar 7;510(1-2):127-34. doi: 10.1016/j.ejphar.2005.01.025.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antipyrine / blood
  • Antipyrine / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Blotting, Western
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochrome P450 Family 2
  • Endotoxins / administration & dosage*
  • Escherichia coli / chemistry
  • Gram-Negative Bacteria / chemistry*
  • Klebsiella pneumoniae / chemistry
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Metabolic Clearance Rate / drug effects
  • Pseudomonas aeruginosa / chemistry
  • Rats
  • Rats, Wistar
  • Steroid 16-alpha-Hydroxylase / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Endotoxins
  • Membrane Proteins
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C11 protein, rat
  • Cyp3a2 protein, rat
  • Cytochrome P-450 CYP3A
  • Cytochrome P450 Family 2
  • Steroid 16-alpha-Hydroxylase
  • Antipyrine