Effect of acetaminophen administration to rats chronically exposed to depleted uranium

Titre du congrès :15th International Conference on Cytochrome P450 Ville du congrès :Bled Date du congrès :17/06/2007

  Background: The extensive use of depleted uranium (DU) in both civilian (nuclear industry, mill tailings, phosphate fertilizers) 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) during 2 to 24 hours at the end of the 9-months 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.
Results: In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group after 24h of treatment (by 56%, p<0.05). In addition, administration of APAP to the DU-exposed rats increased plasma ALT (110%, p<0.01) and AST (135%, p<0.05) more rapidly than in the control group. 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 than for controls. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, was increased by three fold (p<0.01) in the DU-exposed group compared to the controls. In the liver, CYP's activities were decreased between control and DU-exposed rats.
Conclusion: 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.