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Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there a role for HNF4alpha?
Valérie Wauthier1, Roger K Verbeeck, Pedro Buc Calderon
1Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie (PMNT), Département des sciences pharmaceutiques, Université Catholique de Louvain, Avenue E. Mounier 73, 1200, Brussels, Belgium.
Abstract:
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.
Insights
Aging significantly reduces CYP3A2 activity in male rats, with expression changes linked to both post-translational modifications and impaired gene transcription. This involves alterations in hepatocyte nuclear factor 4-alpha (HNF4alpha) levels and DNA binding activity.
Area of Science:
- Pharmacology
- Gerontology
- Molecular Biology
Background:
- CYP3A2 is a male-specific cytochrome P450 isoform.
- Ageing affects drug metabolism and gene expression.
- Growth Hormone (GH) and HNF4alpha play roles in CYP3A2 regulation.
Purpose of the Study:
- To investigate the impact of ageing on CYP3A2 activity and expression in male rats.
- To explore the role of HNF4alpha and GH in age-related CYP3A2 changes.
Main Methods:
- Comparison of CYP3A2 activity (midazolam oxidation) in adult and senescent male rats.
- Assessment of CYP3A2 expression, HNF4alpha protein content, and DNA binding activity.
- Evaluation of HNF4alpha parameters in young male and female rats.
Main Results:
- Senescent male rats showed a 65% decrease in CYP3A2 activity.
- Half of senescent rats had reduced CYP3A2 activity due to post-translational modifications; the other half showed no CYP3A2 expression, indicating transcriptional impairment.
- Senescent rats exhibited a 76% reduction in HNF4alpha protein and decreased DNA binding activity.
- Young female rats had higher HNF4alpha DNA binding activity and protein content than young males.
Conclusions:
- Age-related CYP3A2 suppression in male rats involves both post-translational and transcriptional mechanisms.
- HNF4alpha reduction and altered DNA binding activity contribute to CYP3A2 dysregulation in aging males.
- The suppression of CYP3A2 expression is not solely dependent on HNF4alpha binding activity in senescent male rats.
