1: Exp Gerontol. 2006 Sep;41(9):846-54. Epub 2006 Aug 7.

Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there
a role for HNF4alpha?

Wauthier V, Verbeeck RK, Calderon PB.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie (PMNT),
Departement des sciences pharmaceutiques, Universite Catholique de Louvain,
Avenue E. Mounier 73, 1200, Brussels, Belgium.

The effect of ageing on CYP3A2, a male specific isoform, was examined in adult
(9 months) and senescent (24 months) male rats. A significant decrease (65%) of
CYP3A2-related activity (midazolam oxidation) was observed in all senescent
rats. Half of these rats still express CYP3A2 suggesting that decreased
activities in these rats are due to post-translational modifications. The other
senescent male rats did not express CYP3A2 anymore, indicating an impairment of
transcription. These transcriptional modifications are due to the previously
shown continuous secretion of GH in senescent male rats. GH also regulates
HNF4alpha, a hepatocyte nuclear factor, essential for the basal transcriptional
activation of the CYP3A2 gene. In senescent rats, a drastic reduction (76%) of
HNF4alpha protein content and a decrease in DNA binding activity were observed.
When these parameters were assessed in male and female rats of the same age (3
months), a higher HNF4alpha DNA binding activity and a higher HNF4alpha protein
content (38%) were observed in female rats. Our results show that in male
senescent rats (1) the decrease of HNF4alpha is not consistent with the
continuous secretion of GH, and (2) the suppression of CYP3A2 expression is not
dependent to the HNF4alpha binding activity.

PMID: 16891075 [PubMed - indexed for MEDLINE]

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