title: Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.
abstract: Thalidomide has been reported to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) that are involved in the down-regulation of hepatic cytochrome P450 (CYP) induced by endotoxin. In the present study, we investigated the effects of thalidomide on endotoxin-induced decreases in the activity and expression of hepatic CYP3A2 in rats. Thalidomide (50 mg/kg) was administered orally 22 h and 2 h before intraperitoneal injection of endotoxin (1 mg/kg). Twenty-four hours after the injection of endotoxin, antipyrine clearance experiments were conducted, in which the rats were sacrificed and protein levels of hepatic CYP3A2 were measured. There were no significant differences in the histopathological changes in the liver between the endotoxin-treated and endotoxin plus thalidomide-treated rats. Thalidomide had no effect on the systemic clearance of antipyrine, which is a proper indicator for hepatic CYP3A2 activity, whereas it enhanced endotoxin-induced decrease in the systemic clearance of antipyrine. Western blot analysis revealed that thalidomide had no effect on the protein levels of hepatic CYP3A2, whereas it enhanced the down-regulation of hepatic CYP3A2 by endotoxin. However, there were no significant differences in the concentrations of TNF-alpha and NO in plasma between the endotoxin-treated and endotoxin plus thalidomide-treated rats. The present findings suggest that thalidomide enhances endotoxin-induced decreases in the activity and expression of hepatic CYP3A2.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Ying Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kondo
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takagi
authors.forename: Shinya
authors.initials: S
authors.lastname: Wakusawa
authors.forename: Fumie
authors.initials: F
authors.lastname: Abe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Saito
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004731:Endotoxins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D004364:Pharmaceutical Preparations / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D004731:Endotoxins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D004364:Pharmaceutical Preparations; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A