title: Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, Japan. Electronic address: kaoruk@faculty.chiba-u.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan; Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Takehara
authors.affiliation: Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D006915:Hydroxytestosterones / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D011467:Prostate; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D006915:Hydroxytestosterones; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011944:Receptors, Androgen; D051782:Sterol Regulatory Element Binding Protein 2; D013739:Testosterone; C000607144:AR protein, mouse; C102196:SREBP cleavage-activating protein; C497391:Srebf2 protein, mouse; C025591:6 beta-hydroxytestosterone; C496508:Cyp3a11 protein, mouse
keywords: Androgen receptor; CYP3A; Cholesterol; Cytochrome P450; Prostate; Testosterone