title: Molecular, cellular, and tissue impact of depleted uranium on xenobiotic-metabolizing enzymes.
abstract: Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra-environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure.
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale (LRTOX), Service de Radiobiologie et d'Epidémiologie (SRBE), Pôle de RadioProtection de l'Homme (PRP-HOM), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), B.P. no 17, 92262, Fontenay-aux-Roses Cedex, France, yann.gueguen@irsn.fr.
authors.forename: Yann
authors.initials: Y
authors.lastname: Gueguen
authors.forename: Caroline
authors.initials: C
authors.lastname: Rouas
authors.forename: Audrey
authors.initials: A
authors.lastname: Monin
authors.forename: Line
authors.initials: L
authors.lastname: Manens
authors.forename: Johanna
authors.initials: J
authors.lastname: Stefani
authors.forename: Olivia
authors.initials: O
authors.lastname: Delissen
authors.forename: Stéphane
authors.initials: S
authors.lastname: Grison
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dublineau
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D036401:Toxicity Tests, Chronic; D014502:Uranyl Nitrate / Q000008:administration & dosage / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D015262:Xenobiotics; D014502:Uranyl Nitrate; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A