title: Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis.
abstract: The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B2 but orteronel did not change the expression of HSD3B2, CYP17A1 and AKR1C3. The CYP19A1 activity was not inhibited except by compound IV which lowered activity by 23%. Surprisingly abiraterone caused complete blockade of CYP21A2 activity. Analysis of steroid metabolome by gas chromatography - mass spectrometry revealed changes in steroid levels caused by different inhibitors. We can conclude that orteronel is a highly specific inhibitor of 17,20 lyase activity. The discovery of these specific drug actions on steroidogenic enzyme activities would be valuable for understanding the regulation of androgens.
authors.affiliation: Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, University Children's Hospital Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Udhane
authors.affiliation: Department of Clinical Research, University of Bern, 3010 Bern, Switzerland; Department of Nephrology, Hypertension and Clinical Pharmacology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E 8.1, 66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, University Children's Hospital Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland. Electronic address: amit@pandeylab.org.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D000730:Androstadienes / Q000008:administration & dosage; D000736:Androstenes / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D000728:Androgens; D000730:Androstadienes; D000736:Androstenes; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007093:Imidazoles; D009281:Naphthalenes; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; C571806:orteronel; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
keywords: Abiraterone; CYP17A1; CYP21A2; Castration resistant prostate cancer; Orteronel; PCOS; Premature adrenarche