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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 ?

Uranium affects the drug metabolism: Example of acetaminophen

figure 3

figure 3

Effets of uranium on the toxicity of acetaminophen and pharmacokinetics after treatment with hepatotoxic concentration : CYP : cytochrome P450 ; ALAT : alanine amino transférase ; ASAT : aspartate amino transférase ; NC : non-contaminated ; DU : depleted uranium ; APAP : acetaminophen.

Uranium potentiates the toxicity of acetaminophen administered at a toxic dose

With regard to the effect of chronic uranium contamination on CYP3A, we have put forward the hypothesis that the pharmacokinetics – therefore the bioavailability – of drugs could be modified by this type of contamination and lead to drug-related toxicity or therapeutic inefficacy during drug treatment.

We tested this hypothesis with a potentially hepatotoxic drug treatment, acetaminophen, at a high concentration (400 mg/kg, intraperitoneal injection).

We observed that the animals contaminated with depleted uranium (DU 40 mg/L for 9 months) eliminated plasma acetaminophen levels more quickly than non-contaminated animals. Furthermore, histological kidney changes and a transient increase in liver dysfunction markers such as transaminases were observed more frequently in the DU-exposed group than in the non-exposed group [Gueguen et al. 2007].

This study therefore shows for the first time that chronic uranium contamination disrupts the metabolism of certain drug such as acetaminophen, thus potentiating the toxicity of acetaminophen (Figure 3).

figure 4

figure 4

Effets de l'uranium sur les enzymes de Phase I (CYP3A) et sur la pharmacocinétique du paracétamol administré à une concentration non hépatotoxique CYP : cytochrome P450 ; GAPDH : glycéraldéhyde 3 phosphate déshydrogénase ; APAP : paracétamol ; NC : non contaminé ; UA : uranium appauvri.

The protein expression of CYP 3A is increased during co-exposure to Uranium and Acetaminophen.

A study to determine the effects of a single treatment at a “therapeutic” concentration of acetaminophen was undertaken in animals contaminated with uranium in order to compare the results to the hepatotoxic concentration previously used.

These results show that, under these acetaminophen treatment conditions (50 mg/kg), uranium contamination did not trigger any major change in the metabolism of the medicinal product. Nevertheless, an increase in the protein level of CYP3A2 was observed 3 hours after acetaminophen treatment in animals contaminated with uranium (Figure 4) compared to the non-contaminated animals, [Rouas et al. 2009]. This study confirms that CYP3A2 is targeted by uranium.

 

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references 

Gueguen, Y.,Grandcolas L.,Baudelin C.,Grison S.,Tissandie E.,Jourdain J. R.,Paquet F.,Voisin P.,Aigueperse J.,Gourmelon P.and Souidi M. (2007) Effect of acetaminophen administration to rats chronically exposed to depleted uranium. Toxicology 229, 62-72

Rouas, C.,Souidi M.,Grandcolas L.,Grison S.,Baudelin C.,Gourmelon P.,Pallardy M.and Gueguen Y. (2009) Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure. Environmental Toxicology and Pharmacology 28, 363-369

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