Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat.
The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague-Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7alpha-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARalpha mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics.
Guéguen
Y
Y
Institut de Radioprotection et de Sûreté Nucléaire, Direction de la RadioProtection de l'Homme, Service de Radiobiologie et d'Epidémiologie, IRSN, B.P. No. 17, F 92262 Fontenay-aux-Roses Cedex, France. yann.gueguen@irsn.fr
Souidi
M
M
Baudelin
C
C
Dudoignon
N
N
Grison
S
S
Dublineau
I
I
Marquette
C
C
Voisin
P
P
Gourmelon
P
P
Aigueperse
J
J
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006888:Hydroxycholesterols / Q000097:blood; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014501:Uranium / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism*
D001647:Bile Acids and Salts; D017931:DNA Primers; D006888:Hydroxycholesterols; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics; D014501:Uranium; C011724:cholest-5-en-3 beta,7 alpha-diol; C076996:27-hydroxycholesterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A