Effect of acetaminophen administration to rats chronically exposed to depleted uranium
Résumé
The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination. © 2006 Elsevier Ireland Ltd. All rights reserved.
Mots clés
alanine aminotransferase
aspartate aminotransferase
cytochrome P450 2E1
paracetamol
uranium
animal experiment
animal model
article
controlled study
drug metabolism
enzyme activity
gene expression
histopathology
kidney injury
liver injury
male
nonhuman
nucleotide sequence
priority journal
rat
rat strain
single drug dose
Acetaminophen
Alanine Transaminase
Analgesics
Non-Narcotic
Animals
Aspartate Aminotransferases
Blood Urea Nitrogen
Creatinine
Cytochrome P-450 Enzyme System
Dose-Response Relationship
Drug
Environmental Exposure
Gene Expression Regulation
Enzymologic
Injections
Intraperitoneal
Kidney
Liver
Male
Metabolic Detoxication
Phase I
Phase II
Microsomes
Organ Size
Radioactive Pollutants
Rats
Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Uranyl Nitrate
Weight Loss
Animalia