Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy



Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Genesis of 5α- and 5β-reduced Abi metabolites in patients treated with Abi acetate.
Figure 2: Effects of 5α-reduced Abi metabolites on the androgen pathway and tumour progression.
Figure 3: Long-term exposure to Abi and D4A leads to an increase in SRD5A expression and enzymatic activity and an increase in conversion from D4A to 5α-reduced Abi metabolites.
Figure 4: In patients treated with Abi acetate, SRD5A inhibition significantly increases serum D4A and specifically and significantly depletes all three 5α-Abi metabolites in serum.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray results have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE75387.


  1. Attard, G. et al. Prostate cancer. Lancet 387, 70–82 (2016)

    Article  Google Scholar 

  2. Sharifi, N. Mechanisms of androgen receptor activation in castration-resistant prostate cancer. Endocrinology 154, 4010–4017 (2013)

    Article  CAS  Google Scholar 

  3. Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015)

    Article  ADS  CAS  Google Scholar 

  4. Chang, K. H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013)

    Article  CAS  Google Scholar 

  5. Scher, H. I. & Sawyers, C. L. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J. Clin. Oncol. 23, 8253–8261 (2005)

    Article  CAS  Google Scholar 

  6. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011)

    Article  CAS  Google Scholar 

  7. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013)

    Article  CAS  Google Scholar 

  8. Chang, K. H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 108, 13728–13733 (2011)

    Article  ADS  CAS  Google Scholar 

  9. Russell, D. W. & Wilson, J. D. Steroid 5 α-reductase: two genes/two enzymes. Annu. Rev. Biochem. 63, 25–61 (1994)

    Article  CAS  Google Scholar 

  10. Hirsch, K. S. et al. LY191704: a selective, nonsteroidal inhibitor of human steroid 5 α-reductase type 1. Proc. Natl Acad. Sci. USA 90, 5277–5281 (1993)

    Article  ADS  CAS  Google Scholar 

  11. Clark, R. V. et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J. Clin. Endocrinol. Metab. 89, 2179–2184 (2004)

    Article  CAS  Google Scholar 

  12. Rižner, T. L. et al. Human type 3 3α-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells. Endocrinology 144, 2922–2932 (2003)

    Article  Google Scholar 

  13. Byrne, G. C., Perry, Y. S. & Winter, J. S. Steroid inhibitory effects upon human adrenal 3 β-hydroxysteroid dehydrogenase activity. J. Clin. Endocrinol. Metab. 62, 413–418 (1986)

    Article  CAS  Google Scholar 

  14. Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013)

    Article  CAS  Google Scholar 

  15. Attard, G. et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J. Clin. Endocrinol. Metab. 97, 507–516 (2012)

    Article  CAS  Google Scholar 

  16. Taplin, M. E. et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J. Clin. Oncol. 32, 3705–3715 (2014)

    Article  CAS  Google Scholar 

  17. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015)

    Article  CAS  Google Scholar 

  18. Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl. Med. 6, 254ra125 (2014)

    Article  Google Scholar 

  19. Miyamoto, D. T. et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2, 995–1003 (2012)

    Article  CAS  Google Scholar 

  20. Mostaghel, E. A. et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin. Cancer Res. 17, 5913–5925 (2011)

    Article  CAS  Google Scholar 

  21. Biswas, M. G. & Russell, D. W. Expression cloning and characterization of oxidative 17β- and 3α-hydroxysteroid dehydrogenases from rat and human prostate. J. Biol. Chem. 272, 15959–15966 (1997)

    Article  CAS  Google Scholar 

  22. Mohler, J. L. et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 71, 1486–1496 (2011)

    Article  CAS  Google Scholar 

  23. Papari-Zareei, M., Brandmaier, A. & Auchus, R. J. Arginine 276 controls the directional preference of AKR1C9 (rat liver 3α-hydroxysteroid dehydrogenase) in human embryonic kidney 293 cells. Endocrinology 147, 1591–1597 (2006)

    Article  CAS  Google Scholar 

  24. Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015)

    Article  ADS  CAS  Google Scholar 

  25. Liu, L. L. et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 33, 3140–3150 (2014)

    Article  CAS  Google Scholar 

  26. Hörnberg, E. et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 6, e19059 (2011)

    Article  ADS  Google Scholar 

  27. Deng, W., Wang, Y., Liu, Z., Cheng, H. & Xue, Y. HemI: a toolkit for illustrating heatmaps. PLoS ONE 9, e111988 (2014)

    Article  ADS  Google Scholar 

  28. Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)

    Article  Google Scholar 

  29. Hänzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013)

    Article  Google Scholar 

  30. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

  31. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003)

    Article  ADS  CAS  Google Scholar 

  32. Alyamani, et al. Development and validation of a novel LC–MS/MS method for simultaneous determination of abiraterone and its seven steroidal metabolites in human serum: innovation in separation of diastereoisomers without use of a chiral column. J. Steroid Biochem. Mol. Biol. (2016)

Download references


We thank T. Penning for use of the AKR1C2 construct and D. Russell for LY191704. This work was supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the US Army Medical Research and Materiel Command (PC121382 to Z.L.), a Prostate Cancer Foundation Young Investigator Award (to Z.L.), grants from the National Cancer Institute (P01 CA163227 and P50 CA090381), and a Prostate Cancer Foundation Challenge Award (to S.P.B.). Janssen provided clinical trial support (to M.-E.T.).

Author information

Authors and Affiliations



Z.L. performed gene expression, metabolism and mouse work. M. Alyamani performed mass spectrometry metabolism work. J.L. performed immunoblots. S.K.U. performed chemical syntheses. K.R. and M. Abazeed performed the microarray GSEA analysis. M.-E.T. and S.P.B. designed and performed the clinical trial. Z.L., M. Alaymani, R.J.A. and N.S. designed the studies and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Nima Sharifi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Synthesis of abiraterone metabolites.

a, Synthesis of 5α-Abi, 3α-hydroxy-5α-Abi and 3β-hydroxy-5α-Abi. b, Synthesis of 5β-Abi, 3α-hydroxy-5β-Abi and 3β-hydroxy-5β-Abi. c, Synthesis of D4A.

Extended Data Figure 2 Genesis and interconversion of Abi metabolites.

a, C4-2 cells. b, VCaP cells. Cells were treated with abiraterone or the indicated metabolite (0.1 μM) for 24 or 48 h and each of the indicated metabolites was detected by LC–MS/MS in triplicate. Error bars represent s.d.

Extended Data Figure 3 In vitro time course formation of 5α-reduced Abi metabolites.

ac, Conversion from D4A to 5α-reduced abiraterone metabolites (a), 3-keto reduction of 5α-Abi to 3α-OH-5α-Abi (b), and 3α-OH-oxidation of 3α-OH-5α-Abi to 5α-Abi (c) is detectable in LNCaP and LAPC4 prostate cancer cell lines. Cells were treated with 10 μM of the indicated compounds, metabolites were separated by HPLC and quantified by UV spectroscopy. Experiments were performed in triplicate at least three times and error bars represent s.d. d, Examples of HPLC and UV absorption tracings for incubations of prostate cancer cell lines with D4A, 5α-Abi and 3α-OH-5α-Abi.

Extended Data Figure 4 Clinical presence of 5α-reduced and 5β-reduced Abi metabolites in patients treated with Abi acetate.

a, Dot plot of Abi and its metabolites expressed as the percentage of the total of Abi and its metabolites. b, LC–MS/MS separation of Abi metabolite standards and an example from serum obtained from a patient being treated with Abi.

Extended Data Figure 5 Enzymes involved in the formation of 5α-reduced Abi metabolites.

a, 3βHSD1 catalyses the conversion of Abi to D4A and downstream accumulation of 5α-Abi and 3α-OH-5α-Abi. LAPC4 cells were transiently transfected with the indicated amount of an expression construct encoding 3βHSD1 or vector control before treatment with Abi. b, Conversion of D4A to 5α-Abi is catalysed by SRD5A1 or SRD5A2. The indicated amounts of SRD5A1, SRD5A2, or empty vector plasmids were transfected into 293T cells, and cells were incubated with D4A for the designated incubation times. c, SRD5A1 silencing blocks 5α-reduction of D4A. LAPC4 cells stably expressing short hairpin (sh)RNAs targeting SRD5A1 or nonsilencing control were treated with D4A and metabolites for the indicated times. d, Pharmacological SRD5A inhibition blocks 5α-reduction of D4A. LAPC4 cells were treated with D4A and the SRD5A inhibitors dutasteride or LY191704. A parallel control experiment is shown with inhibition of 5α-reduction of [3H]androstenedione (AD). e, Conversion of 5α-Abi to 3α-OH-5α-Abi is catalysed by AKR1C2. 293T cells were transfected with AKR1C2 or empty vector and treated with 5α-Abi for the indicated times. For all experiments, metabolites were separated by HPLC and quantified by UV spectroscopy (Abi metabolites) or with a beta-RAM ([3H]androgens). Error bars represent s.d. All experiments were performed at least three times.

Extended Data Figure 6 Gene expression profile of stimulation by 5α-Abi and DHT.

a, Unbiased pathway analysis of 5α-abi-regulated genes. b, Gene Set Enrichment Analysis of 5α-abi-regulated genes with the androgen receptor signature gene set. c, Gene expression in LAPC4 cells stimulated by 1 μM 5α-Abi or 0.1 nM DHT for 48 h. Regulated genes were determined by detection P < 0.01, upregulation > 1.55 or downregulation < 0.5 compared with vehicle control group. d, Venn diagram of 5α-abi and DHT-regulated genes.

Extended Data Figure 7 Transcript expression regulation in the presence of Abi, D4A or enzalutamide.

a, SRD5A1 and SRD5A2 expression in VCaP cells treated with Abi or D4A as indicated in Fig. 3. b, SRD5A1 and SRD5A2 expression does not change with enzalutamide (Enz) treatment. c, SRD5A1 protein abundance does not change with enzalutamide treatment in LAPC4 or VCaP cells. d, AR-V7 expression is unchanged in LNCaP cells treated with Abi or D4A as indicated in Fig. 3. Expression was normalized to RPLPO and vehicle-treated cells for all comparisons. Error bars represent s.d.

Extended Data Table 1 Data for each of the 12 patients treated with Abi acetate
Extended Data Table 2 Genes regulated by 5α-abi
Extended Data Table 3 Concentrations of Abi and its metabolites in a phase II clinical trial (NCT01393730)

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Supplementary Table 1. (PDF 625 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Alyamani, M., Li, J. et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533, 547–551 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing