Effect of acetaminophen administration to rats chronically exposed to depleted uranium.
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 (40mg/l) were treated by acetaminophen (APAP, 400mg/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.
Guéguen
Y
Y
Institute for Radiological Protection and Nuclear Safety, Radiological Protection and Human Health Division, Radiobiology and Epidemiology Department, Laboratory of Experimental Toxicology, Fontenay-aux-Roses, France. yann.gueguen@irsn.fr
Grandcolas
L
L
Baudelin
C
C
Grison
S
S
Tissandié
E
E
Jourdain
J R
JR
Paquet
F
F
Voisin
P
P
Aigueperse
J
J
Gourmelon
P
P
Souidi
M
M
D000082:Acetaminophen / Q000008:administration & dosage* / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011848:Radioactive Pollutants / Q000097:blood / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014502:Uranyl Nitrate / Q000097:blood / Q000633:toxicity*; D015431:Weight Loss / Q000187:drug effects
D018712:Analgesics, Non-Narcotic; D011848:Radioactive Pollutants; D014502:Uranyl Nitrate; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase