Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate

Testosterone regulates cellular functions in the prostate through activation of the androgen receptor (AR), which may enhance expression levels of cholesterogenic enzymes through activation of sterol regulatory element-binding protein2 (SREBP2). Because testosterone is inactivated to 6β-hydroxytestosterone by cytochrome P450 3A (CYP3A), we examined the effects of Cyp3a deficiency on circulating testosterone levels and its effects on activation of the AR and expression levels of cholesterogenic enzymes in the prostate using Cyp3a-knockout (Cyp3a(-/-)) mice. The results showed that Cyp3a(-/-) mice had remarkably increased free testosterone levels in plasma along with suppressed testosterone 6β-hydroxylation activities in liver microsomes, suggesting that Cyp3a is a major determinant of systemic levels of testosterone in mice. The results also showed that mRNA expression levels of the AR target genes were increased significantly, and that AR bindings to the promoter region of the AR target genes were more abundant in the prostates of Cyp3a(-/-) mice. These findings suggest that AR activation was stimulated in the prostate of Cyp3a(-/-) mice. In addition, the protein expression levels of SREBP cleavage-activating protein (SCAP), mRNA expression levels of SREBP2 target genes and total cholesterol contents were increased in the prostates of Cyp3a(-/-) mice. The findings suggest that Cyp3a deficiency stimulated the expression of Scap via activation of the AR, which elevated cholesterogenic gene expression levels through activation of SREBP2 and increased total cholesterol contents in the prostate.