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Hepatic effects of depleted uranium on cytochromes P450 implicated in metabolism of bile acids and xenobiotics in rat.

Dublineau I, Souidi M, Combes O, Baudelin C, Dudoignon N, Grison S, Marquette C, and Voisin P , Falk Symposium N° 141, XVIII International Bile Acid Meeting, Bile acid Biology and its therapeutic Implication, June 18-19, 2004, Stockholm, Sweden.

Summary

The toxicity of uranium has been demonstrated for different organs, including kidney, skeleton, central nervous system and liver. The objectives of this present work were thus to evaluate effects of uranium on metabolism of bile acids and xenobiotics in rat liver. In particular, we have studied cytochromes P450 (CYP7A1, CYP27A1, CYP3A1, CYP3A2) and associated nuclear receptors (FXR, PPARa, CAR) implicated in these metabolisms.

The experiments were performed in rats, which received a subcutaneous injection of depleted uranium (11.5 mg/kg). The animals were euthanasied one and three days after contamination. Plasma was collected for determination of 7a- and 27-hydroxycholesterol. The mRNA expression of CYP3A1, CYP3A2 and the nuclear receptors was measured by real-time RT-PCR in liver. Liver microsomal and mitochondrial fractions were also prepared for measurement of enzymatic activities (CYP7A1, CYP27A1).

The 52% decreased plasma level of 7a-hydroxycholesterol observed at three days was associated with a 40% diminution (non significant) of CYP7A1 activity in liver, probably due to the increased expression of FXR (x2) observed at one day. An increased activity (x5) of CYP27A1 was observed at one day. The expression of CYP3A1 was increased by 3-fold at three days, likely due to the increased CAR expression (x3) obtained at day one.

In conclusion, this study demonstrated for the first time that uranium affected the hepatic metabolisms of bile acids and xenobiotics, via effects on cytochromes P450 and some of their nuclear receptors. These effects observed at short term could lead at long term to modifications of hepatic metabolisms of bile acids, vitamin D3 and xenobiotics.


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