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Enhancing Nuclear Safety


Research

The effects on health of chronic contamination with a low dose of radionuclides

(juillet 2011)

RESEARCH allowing the evaluation of radionuclide-related risks and their impact on health

The ENVIRHOM-Santé experimental research programme or Understanding the effects on health of chronic contamination with a low dose of radionuclides

The brain: A new target organ to uranium

Is the xenobiotic detoxification system affected by chronic exposure to uranium ?

Chronic ingestion of caesium 137 in a post-accident situation

Chronic exposure to caesium 137: Experimental and epidemiological studies

Metabolomics: Application in radiotoxicology

The perspectives of the ENVIRHOM-Santé programme

Is the xenobiotic detoxification system affected by chronic exposure to uranium ?

Cytochromes P450 : Targeted by uranium


Uranium, like other heavy metals, can affect the metabolism of xenobiotics [Moore 2004]. The effects of heavy metal contamination (cadmium, chrome, arsenic, etc.) have been described on the induction of the gene coding expression for proteins including P450 cytochromes (CYP2A [Abu-Bakar et al. 2004], CYP1A1 [Miller et al. 2004], and GST [Casalino et al. 2007].

figure 2

figure 2

A summary diagram of the effects of chronic uranium exposure on xenobiotic metabolizing enzymes (CYP: Cytochrome P450; RH: Hydrophobic xenobiotic; R-OH: hydrophilic xenobiotic; R-X: xenobiotic conjugated to a water-soluble element; + : induction of gene expression; = : no effect on gene expression.)

Few studies have examined the effects of depleted uranium (DU) on cytochromes P450 (CYP). These studies mainly concern the administration of a high, toxic concentration of DU. Under these conditions, the expression and activity of different isoforms of CYP are modified, including CYP3A [Gueguen et al. 2006a]. This affects the pharmacokinetics of some drugs (chlorzoxazone, theophylline, ipriflavone) in the case of exposure via the intravenous [Moon et al. 2003] or intratracheal administration [Pasanen et al. 1995].

In the case of chronic oral contamination for 9 months with a non-nephrotoxic concentration of DU (40 mg/L through drinking water), the genetic expression of some phase I enzymes and especially that of CYP3A1 and CYP3A2 is increased in various tissues (liver, kidneys, brain and lungs) whereas the expression of phase II enzymes and phase III transporters does not change (Figure 2) [Gueguen et al. 2005; Souidi et al. 2005]. The CYPs are, therefore, a target of DU under different contamination conditions (acute and chronic) and according to various methods of administration (intravenous injection, intratracheal inhalation and oral absorption).

The gene expression of CYP 3A is modify according to the duration of DU-exposure

A time-lapse uranium contamination study was developed in order to assess changes in this detoxification system over a period ranging from sub-chronic exposure (1 month) to long-term exposure (18 months).

The results show a modify response in the gene expression of CYP3A according to the duration of exposure to DU. No change in gene expression was observed after 1, 3 and 18 months of exposure. After 6 months’ exposure, the gene expression was decreased whereas it was increased after 9 months. These variations over time suggest that adaptation or compensation phenomena probably occur in the body and tissue resulting in a variation in the level of expression of xenobiotic metabolizing enzymes. Moreover, previous study showed that the accumulation of uranium in the tissues in not gradual as a function of time and does not lead to a steady state [Paquet et al. 2006]. The biological variations observed can therefore depend on the concentration of uranium present in the tissues. In fact, more significant effects are observed after 9 months’ contamination – the time during which uranium was present in larger quantities in the liver.

These results corroborate earlier data showing that CYP3A, one of the major xenobiotic metabolizin enzymes, is targeted by uranium.

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references 

Abu-Bakar, A.,Satarug S.,Marks G. C.,Lang M. A.and Moore M. R. (2004) Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA, protein and activity in the mouse: involvement of transcription factor NRF2. Toxicol Lett 148, 199-210

Casalino, E.,Calzaretti G.,Landriscina M.,Sblano C.,Fabiano A.and Landriscina C. (2007) The Nrf2 transcription factor contributes to the induction of alpha-class GST isoenzymes in liver of acute cadmium or manganese intoxicated rats: comparison with the toxic effect on NAD(P)H:quinone reductase. Toxicology 237, 24-34

Gueguen, Y.,Paquet F,Voisin Pand Souidi M (2005). Effects of chronic contamination with depleted uranium on xenobiotic biotransformation enzymes in the rat. Proceedings of the 14th Intl. Conf. on Cytochromes P450.

Gueguen, Y.,Souidi M.,Baudelin C.,Dudoignon N.,Grison S.,Dublineau I.,Marquette C.,Voisin P.,Gourmelon P.and Aigueperse J. (2006a) Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat. Arch Toxicol 80, 187-95

Miller, A. C.,Brooks K.,Smith J.and Page N. (2004) Effect of the militarily-relevant heavy metals, depleted uranium and heavy metal tungsten-alloy on gene expression in human liver carcinoma cells (HepG2). Mol Cell Biochem 255, 247-56

Moon, Y. J.,Lee A. K.,Chung H. C.,Kim E. J.,Kim S. H.,Lee D. C.,Lee I.,Kim S. G.and Lee M. G. (2003) Effects of acute renal failure on the pharmacokinetics of chlorzoxazone in rats. Drug Metab Dispos 31, 776-84

Paquet, F.,Houpert P.,Blanchardon E.,Delissen O.,Maubert C.,Dhieux B.,Moreels A. M.,Frelon S.and Gourmelon P. (2006) Accumulation and distribution of uranium in rats after chronic exposure by ingestion. Health Phys 90, 139-47

Pasanen, M.,Lang S.,Kojo A.and Kosma V. M. (1995) Effects of simulated nuclear fuel particles on the histopathology and CYP enzymes in the rat lung and liver. Environ Res 70, 126-33

Souidi, M.,Gueguen Y.,Linard C.,Dudoignon N.,Grison S.,Baudelin C.,Marquette C.,Gourmelon P.,Aigueperse J.and 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, 113-122

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