Archives of Toxicology

, Volume 80, Issue 8, pp 473–480 | Cite as

Effects of depleted uranium after short-term exposure on vitamin D metabolism in rat

  • E. Tissandie
  • Y. Guéguen
  • J. M. A. Lobaccaro
  • F. Paquet
  • J. Aigueperse
  • M. SouidiEmail author
Inorganic Compounds


Uranium is a natural radioactive heavy metal. Its toxicity has been demonstrated for different organs, including bone, kidney, liver and brain. Effects of an acute contamination by depleted uranium (DU) were investigated in vivo on vitamin D3 biosynthetic pathway. Rats received an intragastric administration of DU (204 mg/kg) and various parameters were studied either on day 1 or day 3 after contamination. Cytochrome P450 (CYP27A1, CYP2R1, CYP27B1, CYP24A1) enzymes involved in vitamin D metabolism and two vitamin D3-target genes (ECaC1, CaBP-D9K) were assessed by real time RT-PCR in liver and kidneys. CYP27A1 activity was measured in liver and vitamin D and parathyroid hormone (PTH) level were measured in plasma. In acute treated-rats, vitamin D level was increased by 62% and decreased by 68% in plasma, respectively at day 1 and at day 3, which paralleled with a concomitant decrease of PTH level (90%) at day 3. In liver, cyp2r1 mRNA level was increased at day 3. Cyp27a1 activity decreased at day 1 and increased markedly at day 3. In kidney, cyp27b1 mRNA was increased at days 1 and 3 (11- and 4-fold respectively). Moreover, ecac1 and cabp-d9k mRNA levels were increased at day 1 and decreased at day 3. This work shows for the first time that DU acute contamination modulates both activity and expression of CYP enzymes involved in vitamin D metabolism in liver and kidney, and consequently affects vitamin D target genes levels.


Depleted uranium Cytochrome P450 Vitamin D3 



1α,25-dihydroxyvitamin D3


25-hydroxyvitamin D3




Constitutive androstane receptor


Cytochrome P450


Depleted uranium


Epithelial Ca2+ channel 1


Hepatocyte nuclear factor


Peroxisome proliferator activated receptor


Parathyroid hormone


Pregnane X receptor


Retinoid X receptor


Vitamin D receptor



The authors thank C. Baudelin and N. Dudoignon for animal’s experimentation and L. Grandcolas, I. Dublineau and C. Linard for helpful assistance and invaluable advice. This study was part of the ENVIRHOM research program supported by the Institute for Radioprotection and Nuclear Safety (IRSN). J.M.A. Lobaccaro is a Professor of the Université Blaise Pascal and is supported by the Centre National de la Recherche Scientifique, the Université Blaise Pascal, the Fondation pour la Recherche Médicale #INE2000-407031/1, the Fondation BNP-Paribas.


  1. Anderson PH, O’Loughlin PD, May BK, Morris HA (2003) Quantification of mRNA for the vitamin D metabolizing enzymes CYP27B1 and CYP24 and vitamin D receptor in kidney using real-time reverse transcriptase–polymerase chain reaction. J Mol Endocrinol 31:123–132PubMedCrossRefGoogle Scholar
  2. Anderson PH, O’Loughlin PD, May BK, Morris HA (2004) Determinants of circulating 1,25-dihydroxyvitamin D3 levels: the role of renal synthesis and catabolism of vitamin D. J Steroid Biochem Mol Biol 89–90:111–113PubMedCrossRefGoogle Scholar
  3. Anderson PH, O’Loughlin PD, May BK, Morris HA (2005) Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)2D3 levels. Bone 36:654–662PubMedCrossRefGoogle Scholar
  4. Armbrecht HJ, Hodam TL, Boltz MA (2003) Hormonal regulation of 25-hydroxyvitamin D3-1alpha-hydroxylase and 24-hydroxylase gene transcription in opossum kidney cells. Arch Biochem Biophys 409:298–304PubMedCrossRefGoogle Scholar
  5. Bem H, Bou-Rabee F (2004) Environmental and health consequences of depleted uranium use in the 1991 Gulf War. Environ Int 30:123–134PubMedCrossRefGoogle Scholar
  6. Berglund M, Akesson A, Bjellerup P, Vahter M (2000) Metal–bone interactions. Toxicol Lett 112–113:219–225PubMedCrossRefGoogle Scholar
  7. Bleise A, Danesi PR, Burkart W (2003) Properties, use and health effects of depleted uranium (DU): a general overview. J Environ Radioact 64:93–112PubMedCrossRefGoogle Scholar
  8. Brenza HL, DeLuca HF (2000) Regulation of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression by parathyroid hormone and 1,25-dihydroxyvitamin D3. Arch Biochem Biophys 381:143–152PubMedCrossRefGoogle Scholar
  9. Brown AJ, Dusso A, Slatopolsky E (1999) Vitamin D. Am J Physiol 277:F157–F175PubMedGoogle Scholar
  10. Brzoska MM, Moniuszko-Jakoniuk J (2005) Effect of low-level lifetime exposure to cadmium on calciotropic hormones in aged female rats. Arch Toxicol 79(11):636–646PubMedCrossRefGoogle Scholar
  11. Cao LP, Bolt MJ, Wei M, Sitrin MD, Chun Li Y (2002) Regulation of calbindin-D9k expression by 1,25-dihydroxyvitamin D(3) and parathyroid hormone in mouse primary renal tubular cells. Arch Biochem Biophys 400:118–124PubMedCrossRefGoogle Scholar
  12. Carafoli E, Tiozzo R, Pasquali-Ronchetti I, Laschi R (1971) A study of Ca 2+ metabolism in kidney mitochondria during acute uranium intoxication. Lab Invest 25:516–527PubMedGoogle Scholar
  13. Chen KS, DeLuca HF (1995) Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta 1263:1–9PubMedGoogle Scholar
  14. Chen W, Chiang JY (2003) Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha). Gene 313:71–82PubMedCrossRefGoogle Scholar
  15. Chung W, Kim EJ, Lee I, Kim SG, Lee MG, Kim SH (2003) Effects of recombinant human growth hormone on the pharmacokinetics of intravenous chlorzoxazone in rats with acute renal failure induced by uranyl nitrate. Life Sci 73:253–263PubMedCrossRefGoogle Scholar
  16. den Dekker E, Hoenderop JG, Nilius B, Bindels RJ (2003) The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell Calcium 33:497–507CrossRefGoogle Scholar
  17. Domingo JL (2001) Reproductive and developmental toxicity of natural and depleted uranium: a review. Reprod Toxicol 15:603–609PubMedCrossRefGoogle Scholar
  18. Domingo JL, Llobet JM, Tomas JM, Corbella J (1987) Acute toxicity of uranium in rats and mice. Bull Environ Contam Toxicol 39:168–174PubMedCrossRefGoogle Scholar
  19. Dublineau I, Grison S, Linard C, Baudelin C, Dudoignon N, Souidi M, Marquette C, Paquet F, Aigueperse J, Gourmelon P (2005) Short-term effects of depleted uranium on mucosal immunity in rat intestine. J Toxicol Environ Health A (in press)Google Scholar
  20. Gueguen Y, Souidi M, Baudelin C, Dudoignon N, Grison S, Dublineau I, Marquette C, Voisin P, Gourmelon P, Aigueperse J (2005) Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat. Arch Toxicol 1–9Google Scholar
  21. Haley DP (1982) Morphologic changes in uranyl nitrate-induced acute renal failure in saline- and water-drinking rats. Lab Invest 46:196–208PubMedGoogle Scholar
  22. Kurttio P, Komulainen H, Leino A, Salonen L, Auvinen A, Saha H (2005) Bone as a possible target of chemical toxicity of natural uranium in drinking water. Environ Health Perspect 113:68–72PubMedCrossRefGoogle Scholar
  23. La Touche YD, Willis DL, Dawydiak OI (1987) Absorption and biokinetics of U in rats following an oral administration of uranyl nitrate solution. Health Phys 53:147–162PubMedCrossRefGoogle Scholar
  24. Leggett RW (1989) The behavior and chemical toxicity of U in the kidney: a reassessment. Health Phys 57:365–383PubMedGoogle Scholar
  25. Lestaevel P, Houpert P, Bussy C, Dhieux B, Gourmelon P, Paquet F (2005) The brain is a target organ after acute exposure to depleted uranium. Toxicology 212:219–226PubMedCrossRefGoogle Scholar
  26. Lewin E, Garfia B, Recio FL, Rodriguez M, Olgaard K (2002) Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation. J Am Soc Nephrol 13:2110–2116PubMedCrossRefGoogle Scholar
  27. Li YC, Pirro AE, Demay MB (1998) Analysis of vitamin D-dependent calcium-binding protein messenger ribonucleic acid expression in mice lacking the vitamin D receptor. Endocrinology 139:847–851PubMedCrossRefGoogle Scholar
  28. McClain DE, Benson KA, Dalton TK, Ejnik J, Emond CA, Hodge SJ, Kalinich JF, Landauer MA, Miller AC, Pellmar TC, Stewart MD, Villa V, Xu J (2001) Biological effects of embedded depleted uranium (DU): summary of armed forces radiobiology research institute research. Sci Total Environ 274:115–118PubMedCrossRefGoogle Scholar
  29. Mehta RG, Mehta RR (2002) Vitamin D and cancer. J Nutr Biochem 13:252–264PubMedCrossRefGoogle Scholar
  30. Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360:1155–1162PubMedCrossRefGoogle Scholar
  31. Pasanen M, Lang S, Kojo A, Kosma VM (1995) Effects of simulated nuclear fuel particles on the histopathology and CYP enzymes in the rat lung and liver. Environ Res 70:126–133PubMedCrossRefGoogle Scholar
  32. Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM (2001) Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol 21:1840–1845PubMedCrossRefGoogle Scholar
  33. Prosser DE, Jones G (2004) Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci 29:664–673PubMedCrossRefGoogle Scholar
  34. Quinn CM, Jessup W, Wong J, Kritharides L, Brown AJ (2005) Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPARgamma ligands. Biochem J 385:823–830PubMedCrossRefGoogle Scholar
  35. Rao YP, Vlahcevic ZR, Stravitz RT, Mallonee DH, Mullick J, Avadhani NG, Hylemon PB (1999) Down-regulation of the rat hepatic sterol 27-hydroxylase gene by bile acids in transfected primary hepatocytes: possible role of hepatic nuclear factor 1alpha. J Steroid Biochem Mol Biol 70:1–14PubMedCrossRefGoogle Scholar
  36. Rodriguez-Martinez MA, Garcia-Cohen EC (2002) Role of Ca(2+) and vitamin D in the prevention and treatment of osteoporosis. Pharmacol Ther 93:37–49PubMedCrossRefGoogle Scholar
  37. Ropenga A, Chapel A, Vandamme M, Griffiths NM (2004) Use of reference gene expression in rat distal colon after radiation exposure: a caveat. Radiat Res 161:597–602PubMedCrossRefGoogle Scholar
  38. Souidi M, Parquet M, Lutton C (1998) Improved assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by the use of hydroxypropyl-beta-cyclodextrin and an NADPH-regenerating system. Clin Chim Acta 269:201–217PubMedCrossRefGoogle Scholar
  39. Souidi M, Parquet M, Ferezou J, Lutton C (1999) Modulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities by steroids and physiological conditions in hamster. Life Sci 64:1585–1593PubMedCrossRefGoogle Scholar
  40. Souidi M, Gueguen Y, Linard C, Dudoignon N, Grison S, Baudelin C, Marquette C, Gourmelon P, Aigueperse J, Dublineau I (2005) In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear receptors PXR and CAR in the rat. Toxicology 214:113–122PubMedCrossRefGoogle Scholar
  41. Stefanovic V, Ivic MA, Strahinjic S (1987) Calcium and phosphate metabolism in uranyl nitrate-induced acute renal failure. Arch Int Physiol Biochim 95:223–228PubMedGoogle Scholar
  42. Su T, Waxman DJ (2004) Impact of dimethyl sulfoxide on expression of nuclear receptors and drug-inducible cytochromes P450 in primary rat hepatocytes. Arch Biochem Biophys 424:226–234PubMedCrossRefGoogle Scholar
  43. Wang L, Klopot A, Freund JN, Dowling LN, Krasinski SD, Fleet JC (2004) Control of differentiation-induced calbindin-D9k gene expression in Caco-2 cells by cdx-2 and HNF-1alpha. Am J Physiol Gastrointest Liver Physiol 287:G943–G953PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • E. Tissandie
    • 1
  • Y. Guéguen
    • 1
  • J. M. A. Lobaccaro
    • 2
  • F. Paquet
    • 1
  • J. Aigueperse
    • 1
  • M. Souidi
    • 1
    Email author
  1. 1. Radiological Protection and Human health Division, Radiobiology and Epidemiology Department, Laboratory of Experimental ToxicologyInstitute for Radiological protection and Nuclear SafetyFontenay-aux-Roses CedexFrance
  2. 2.Compared Physiology and Molecular EndocrinologyUMR Université Blaise Pascal-CNRSAubière CedexFrance

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