Molecular Aspect of Cytochrome P450 3A1 and 3A2 regulated by Dexamethasone and Testosterone

• Main Authors: Pao-Sung Li, 李寶松
• Other Authors: Fu-Chuo Peng
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/54799852115181911914

碩士 === 臺灣大學 === 毒理學研究所 === 95 === Cytochrome P450s are important Phase I enzymes. CYP3A subfamily enzymes are involved in metabolism of many xenobiotics and drugs and induced by substances of large structural diversity. In rat liver, CYP3A1 and CYP3A2 are major CYP3A enzymes. The former is induced intensely by dexamethasone but the latter is just induced slightly. It was reported that induction of CYP3A by dexamethasone is not through classical glucocorticoid receptor pathway but some orphan nuclear receptors. Recently it was regarded that pregnane X receptor (PXR) should play an important role in CYP3A induction. PXR binds to its ligand and then enter nucleus to interact with CYP3A gene promoter to activate transcription. CYP3A2 is belong to the male specicic enzyme, so it expresses in adult male rat liver but hardly in adult rat liver. The sexual dimorphism is due to involvement of androgen in regulating CYP3A2 expression. It was reported that androgen regulate CYP3A2 expression by influencing growth hormone secretion profiles but the molecular mechanism is not yet so clear. To explore which nuclear receptors are involved in CYP3A induction, rats were treated dexamethasone and the nuclear receptors were detected. To explore whether androgen receptor is involved in CYP3A2 regulation by testosterone, castrated male rats were treated tesetosterone and androgen receptor antagonist flutamide and CYP3A2 expression was detected. To explore whether testosterone regulate CYP3A2 directly, cultured rat hepatoma cells were treated DHT and CYP3A2 expression was detected. The results indicated: (1)nuclear receptors such as PXR and HNF-4α should play an important role in CYP3A induction by dexamethasone. (2)In vitro and in vivo study indicated that AR protein had strongly down-regulation effect by dexamethasone. It was reported that dexamethasone could interact with AR gene through GR. (3)In vitro cell culture study indicated DHT did not have induction effects on CYP3A2 expression and it is suggested that CYP3A2 expression regulation by androgen should be direct mechanism.