Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there a role for HNF4alpha?
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.
Wauthier
Valérie
V
Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie (PMNT), Département des sciences pharmaceutiques, Université Catholique de Louvain, Avenue E. Mounier 73, 1200, Brussels, Belgium.
Verbeeck
Roger K
RK
Calderon
Pedro Buc
PB
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis* / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000032:analysis; D051544:Cytochrome P-450 CYP3A; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005260:Female; D013006:Growth Hormone / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000032:analysis* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000031:analogs & derivatives / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors
D051837:COUP Transcription Factor II; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D008565:Membrane Proteins; D012333:RNA, Messenger; C042940:4-hydroxymidazolam; D013006:Growth Hormone; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam