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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 ?


Caroline Rouas, PhD1, present adress : L'Oréal, France

Yann Gueguen, Researcher at the Experimental radiotoxicology laboratory (LRTOX)

The xenobiotic metabolizing enzymes: an essential role in detoxification


The xenobiotic metabolizing enzymes 2 have a primary role in protection against harmful insult from the environment. Playing a key role in the metabolism and elimination of potentially toxic compounds, any change in their regulation, expression and/or their activity may have harmful effects on the body. It has already been shown that this system is a target for certain heavy metals toxicity such as cadmium [Moore 2004]. Concerning uranium - a heavy metal naturally present in the environment - the effects have not been fully elucidated to date.

The role of enzyme detoxification

The human body like that of other animal species is frequently exposed to potentially toxic compounds and is capable of actively metabolising numerous foreign substances such as chemical pollutants, drugs and other xenobiotics. Xenobiotic metabolizing enzymes including cytochromes P450 (CYP), play a key role in biotransformation, metabolism and/or the detoxification of foreign compounds [Gueguen et al 2006b].

figure 1

figure 1

Phase I enzymes (essentially the cytochromes P450), so-called functionalizing enzymes, essentially catalyse oxido-reduction and hydrolysis reactions. Phase II enzymes (glutathion-S-transferases or GST, UDP glucuronosyl transferases or UGT…), so-called conjugating enzymes, catalyse conjugation reactions.

Generally, after functionalisation, phase III transporters (P-glycoprotein or Pgp, multidrug resistance proteins or MRP…) transport xenobiotics and their metabolites through the membranes in order to eliminate them from the cell (Figure 1). 

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References and definitions

1 :  Caroline Rouas carried out her research studies at IRSN. She submitted her thesis on 01 October 2010 on sur l'étude des mécanismes mis en jeu lors d’une exposition à l’uranium appauvri sur le système de détoxification in vivo et in vitro (study of the mechanisms involved on exposing in-vivo and in-vitro drug metabolism to uranium).

2 : A xenobiotic is a generally hydrophobic compound. The liver is the main organ involved in their metabolism and elimination. To do this, it is composed with three groups of proteins. Phase I enzymes, the so-called functionalisation enzymes, in which P450 cytochromes (CYP) play a major role, are located on the surface of the endoplasmic reticulum. The active site of the CYP contains an iron (Fe) atom surrounded by nitrogen atoms (N). The organic compound is oxidised and a molecular oxygen atom is incorporated into the chemical product (-OH). The main phase II enzymes, the so-called conjugating enzymes, are divided into three sub-groups: Glutathion S transferases (GST), UDPglucuronosyl transferases (UGT) and sulfotransferases (SULT). They are involved in transforming the compound by adding a hydrophilic compound. The phase III transporters (MDR: multi drug resistance protein, MRP: multi drug resistance-associated protein) aim to eliminate the compound which is rendered water-soluble, outside the cell, towards the blood system in order for it to be eliminated in the urine through the kidneys.

Gueguen, Y.,Mouzat K.,Ferrari L.,Tissandie E.,Lobaccaro J. M.,Batt A. M.,Paquet F.,Voisin P.,Aigueperse J.,Gourmelon P.and Souidi M. (2006b) [Cytochromes P450: xenobiotic metabolism, regulation and clinical importance]. Ann Biol Clin (Paris) 64, 535-48

Moore, M. R. (2004) A commentary on the impacts of metals and metalloids in the environment upon the metabolism of drugs and chemicals. Toxicol Lett 148, 153-8

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