Induction of CYP2C12 expression in senescent male rats is well correlated to an increase of HNF3beta expression, while the decline of CYP2C11 expression is unlikely due to a decrease of STAT5 activation.
Ageing affects drugs metabolism influencing the therapeutic efficacy and safety of drugs. By using the experimental model of aged male rats, we investigated the influence of ageing on some CYP2C isoforms, the most important CYP450 sub-family in rats. The activity of the male specific CYP2C11 is decreased by 55% in senescent male rats. This correlates with a significant reduction of both protein content (80%) and mRNA (60%) indicating a demasculinization process. The expression of CYP2C12, a female specific isoform, is induced in senescent male rats indicating a feminization process. Neither the activity nor the expression of CYP2C6, a female predominant isoform, is modified in senescent male rats. Thereafter, certain putative GH mediators like some liver enriched transcription factors (LETFs) or STAT5b were investigated. The amount of HNF3beta mRNA, a transcription factor involved in the up-regulation of CYP2C12, has been shown to increase by about three-fold in senescent male rats. With regard to STAT5b, which has been reported to be involved in the male specific regulation of CYP2C11, large amounts of phosphorylated STAT5 were observed in the liver of senescent male rats. These results indicate that while the induction of CYP2C12 during ageing could be due, at least partially, to the enhanced HNF3beta expression, the decline of CYP2C11 is unlikely related to a decrease of STAT5 activation.
Wauthier
Valérie
V
Unité de Pharmacocinétique, Métabolisme, Nutrition, et Toxicologie (PMNT), Département des sciences pharmaceutiques, Université Catholique de Louvain, Brussels, Belgium.
Dubois
Pascaline
P
Verbeeck
Roger K
RK
Calderon
Pedro Buc
PB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013223:Statistics as Topic; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000096:biosynthesis*
D050799:STAT5 Transcription Factor; D051542:Hepatocyte Nuclear Factor 3-beta; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C034694:steroid 15-beta-hydroxylase