Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.
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.
Ueyama
Jun
J
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
Nadai
Masayuki
M
Zhao
Ying Lan
YL
Kanazawa
Hiroaki
H
Takagi
Kenji
K
Kondo
Takaaki
T
Takagi
Kenzo
K
Wakusawa
Shinya
S
Abe
Fumie
F
Saito
Hiroko
H
Miyamoto
Ken-Ichi
K
Hasegawa
Takaaki
T
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
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