1: Biochem Pharmacol. 2007 Apr 1;73(7):923-33. Epub 2006 Dec 15.

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.

Wauthier V, Dubois P, Verbeeck RK, Calderon PB.

Unite de Pharmacocinetique, Metabolisme, Nutrition, et Toxicologie (PMNT),
Departement des sciences pharmaceutiques, Universite Catholique de Louvain,
Bruxelles, Belgium.

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.

PMID: 17239351 [PubMed - in process]

Related Links

    Inhibitory cross-talk between STAT5b and liver nuclear factor HNF3beta:
impact on the regulation of growth hormone pulse-stimulated, male-specific liver
cytochrome P-450 gene expression. [J Biol Chem. 2001] PMID:11562369
    
    Synergistic action of hepatocyte nuclear factors 3 and 6 on CYP2C12 gene
expression and suppression by growth hormone-activated STAT5b. Proposed model
for female specific expression of CYP2C12 in adult rat liver. [J Biol Chem.
2000] PMID:10931833
    
    Possible involvement of truncated signal transducer and activator of
transcription-5 in the GH pattern-dependent regulation of CYP2C12 gene
expression in rat liver. [Mol Endocrinol. 2002] PMID:12089354
    
    Effects of bile duct ligation on hepatic expression of female-specific
CYP2C12 in male and female rats. [Hepatology. 1998] PMID:9731550
    
    Effects of chronic ethanol on hepatic and renal CYP2C11 in the male rat:
interactions with the Janus-kinase 2-signal transducer and activators of
transcription proteins 5b pathway. [Endocrinology. 2003] PMID:12933671