title: 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.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Iwase
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Toyoharu
authors.initials: T
authors.lastname: Yokoi
authors.forename: Kenji
authors.initials: K
authors.lastname: Baba
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takagi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004731:Endotoxins / Q000008:administration & dosage*; D004926:Escherichia coli / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000737:chemistry*; D007711:Klebsiella pneumoniae / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D004731:Endotoxins; D008565:Membrane Proteins; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D000983:Antipyrine