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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 causes gene modifications in xenobiotic metabolism enzymes


All of these results tend to show that chronic uranium contamination (40 mg/L, for 9 months) only triggers a major change in the pharmacokinetic profile of acetaminophen if the latter is administered at a toxic concentration (400 mg/kg, intraperitoneal injection).

In view of these results, a third treatment scheme has been realized in order to estimate the effects of chronic uranium contamination within the scope of repeated acetaminophen treatment at a therapeutic concentration. This third experiment should provide conclusive information on the effects of uranium in the case of a standard therapeutic regimen.

Moreover, mechanistic studies have been launched in order to establish whether the variations of gene/protein expression of CYP3A are the result of the direct effects of uranium on gene, protein or enzymatic regulation at cell level. An in-vitro approach has been adopted with regard to a reference model of human hepatocytoma cell line (HepG2) and primary human hepatocytes. The absence of any DU-mediated effects on CYP3A in these in-vitro models suggests that uranium acts via an indirect effect, which could be due to the consequences of disruptions involving other systems such as those related to hormones or inflammatory processes. Additional studies should enable us to determine their role.

To conclude, chronic exposure to a low dose of uranium mainly induces gene-relared changes of xenobiotic metabolizing enzymes (including CYP3A in particular). These changes are regulated by a series of complex mechanisms that have yet to be elucidated. However, they are not sufficiently important to trigger major changes in the metabolism of acetaminophen when the latter is administered at non-hepatotoxic doses.

 

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