Connor Wright1, Patrick O'Day1, Mohammed Alyamani2, Nima Sharifi2,3,4, Richard J Auchus1,5. 1. Division of Metabolism, Diabetes, and Endocrinology, Department of Internal Medicine. 2. Genitourinary Malignancies Research Center, Lerner Research Institute. 3. Department of Urology, Glickman Urological and Kidney Institute. 4. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA. 5. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
Abstract
CONTEXT: The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. OBJECTIVE: To test the hypothesis that AA therapy decreases 11-oxygenated androgens. DESIGN: Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. METHODS: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. RESULTS: In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline. CONCLUSIONS: We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.
CONTEXT: The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. OBJECTIVE: To test the hypothesis that AA therapy decreases 11-oxygenated androgens. DESIGN: Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. METHODS: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. RESULTS: In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline. CONCLUSIONS: We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.
Authors: Francis K Yoshimoto; Yishan Zhou; Hwei-Ming Peng; David Stidd; Jennifer A Yoshimoto; Kamalesh K Sharma; Susan Matthew; Richard J Auchus Journal: Biochemistry Date: 2012-08-27 Impact factor: 3.162
Authors: Richard J Auchus; Elizabeth O Buschur; Alice Y Chang; Gary D Hammer; Carole Ramm; David Madrigal; George Wang; Martha Gonzalez; Xu Steven Xu; Johan W Smit; James Jiao; Margaret K Yu Journal: J Clin Endocrinol Metab Date: 2014-04-29 Impact factor: 5.958
Authors: Adina F Turcu; Aya T Nanba; Robert Chomic; Sunil K Upadhyay; Thomas J Giordano; James J Shields; Deborah P Merke; William E Rainey; Richard J Auchus Journal: Eur J Endocrinol Date: 2016-02-10 Impact factor: 6.664
Authors: Charles J Ryan; Matthew R Smith; Johann S de Bono; Arturo Molina; Christopher J Logothetis; Paul de Souza; Karim Fizazi; Paul Mainwaring; Josep M Piulats; Siobhan Ng; Joan Carles; Peter F A Mulders; Ethan Basch; Eric J Small; Fred Saad; Dirk Schrijvers; Hendrik Van Poppel; Som D Mukherjee; Henrik Suttmann; Winald R Gerritsen; Thomas W Flaig; Daniel J George; Evan Y Yu; Eleni Efstathiou; Allan Pantuck; Eric Winquist; Celestia S Higano; Mary-Ellen Taplin; Youn Park; Thian Kheoh; Thomas Griffin; Howard I Scher; Dana E Rathkopf Journal: N Engl J Med Date: 2012-12-10 Impact factor: 91.245
Authors: Michael W O'Reilly; Punith Kempegowda; Carl Jenkinson; Angela E Taylor; Jonathan L Quanson; Karl-Heinz Storbeck; Wiebke Arlt Journal: J Clin Endocrinol Metab Date: 2017-03-01 Impact factor: 5.958
Authors: Angela Davio; Helen Woolcock; Aya T Nanba; Juilee Rege; Patrick O'Day; Jianwei Ren; Lili Zhao; Hiroki Ebina; Richard Auchus; William E Rainey; Adina F Turcu Journal: J Clin Endocrinol Metab Date: 2020-08-01 Impact factor: 5.958
Authors: Hedi L Claahsen-van der Grinten; Phyllis W Speiser; S Faisal Ahmed; Wiebke Arlt; Richard J Auchus; Henrik Falhammar; Christa E Flück; Leonardo Guasti; Angela Huebner; Barbara B M Kortmann; Nils Krone; Deborah P Merke; Walter L Miller; Anna Nordenström; Nicole Reisch; David E Sandberg; Nike M M L Stikkelbroeck; Philippe Touraine; Agustini Utari; Stefan A Wudy; Perrin C White Journal: Endocr Rev Date: 2022-01-12 Impact factor: 19.871
Authors: Yuta Tezuka; Nanako Atsumi; Amy R Blinder; Juilee Rege; Thomas J Giordano; William E Rainey; Adina F Turcu Journal: J Clin Endocrinol Metab Date: 2021-04-23 Impact factor: 5.958
Authors: Brittany K Wise-Oringer; Anne Claire Burghard; Patrick O'Day; Abeer Hassoun; Aviva B Sopher; Ilene Fennoy; Kristen M Williams; Patricia M Vuguin; Renu Nandakumar; Donald J McMahon; Richard J Auchus; Sharon E Oberfield Journal: Horm Res Paediatr Date: 2021-02-02 Impact factor: 2.852
Authors: Gido Snaterse; Lisanne F van Dessel; Job van Riet; Angela E Taylor; Michelle van der Vlugt-Daane; Paul Hamberg; Ronald de Wit; Jenny A Visser; Wiebke Arlt; Martijn P Lolkema; Johannes Hofland Journal: JCI Insight Date: 2021-06-08
Authors: James P Teuber; Kazutaka Nanba; Adina F Turcu; Xuan Chen; Lili Zhao; Tobias Else; Richard J Auchus; William E Rainey; Juilee Rege Journal: J Steroid Biochem Mol Biol Date: 2021-06-02 Impact factor: 5.011
Authors: Henry H Moon; Katrina L Clines; Patrick J O'Day; Basel M Al-Barghouthi; Emily A Farber; Charles R Farber; Richard J Auchus; Gregory A Clines Journal: J Bone Miner Res Date: 2021-05-18 Impact factor: 6.390
Authors: Jenny A Visser; Johannes Hofland; Gido Snaterse; Rosinda Mies; Wytske M van Weerden; Pim J French; Johan W Jonker; Adriaan B Houtsmuller; Martin E van Royen Journal: Prostate Cancer Prostatic Dis Date: 2022-01-19 Impact factor: 5.455