Ageing is associated with increased expression but decreased activity of CYP2E1 in male Wistar rats.
The effect of ageing on CYP2E1 activity and its protein and mRNA contents was investigated in both adult (9 months) and senescent (24 months) male Wistar rats. The CYP2E1 activity (as measured by chlorzoxazone hydroxylation) was significantly decreased by 36% in senescent rats as compared to adult rats. However, this decrease of activity was not associated with a loss of protein content because the amount of both CYP2E1 protein and CYP2E1 mRNA did not decrease in senescent rats but rather increased, by 79% and 64% respectively, as compared to adult rats. Lipid peroxidation was increased significantly by 140% with ageing. The decrease in CYP2E1 activity could be explained by post-translational modification of CYP2E1 proteins, due to an increase in oxidative stress in senescent animals, leading to a loss of their functionality. However, no changes in the extent of protein carbonyls were observed in the adult versus senescent rats (16.2 +/- 9.6 vs. 12.7 +/- 7.3 nmol/mg prot) and the major proteasome activity remained unchanged. With regards to the increase of CYP2E1 expression, our results showed that the amount of hepatocyte nuclear factor 1alpha mRNA, a transcription factor that positively regulates CYP2E1, was strongly increased (154%) in senescent rats.
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.
Schenten
Véronique
V
Verbeeck
Roger K
RK
Calderon
Pedro Buc
PB
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002753:Chlorzoxazone / Q000737:chemistry / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D051538:Hepatocyte Nuclear Factor 1-alpha; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D046988:Proteasome Endopeptidase Complex; D002753:Chlorzoxazone