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.