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CYP17A1
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<h2 id="structure">Structure</h2> <h3>Gene</h3> <p>The <i>CYP17A1</i> gene resides on chromosome 10 at the band 10q24.3 and contains 8 <a href="/facts/Exon/8KWJtLuN">exons</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> The <a href="/facts/CDNA/P2nWeY4T">cDNA</a> of this gene spans a length of 1527 <a href="/facts/Base_pair/xmPpPQ9W">bp</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> This gene encodes a member of the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> superfamily of enzymes. The cytochrome P450 proteins are generally regarded as <a href="/facts/Monooxygenase/aP46fepz">monooxygenases</a> that catalyze many reactions involved in drug metabolism and synthesis of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>, <a href="/facts/Steroid/4AhMbgXt">steroids</a>, and other <a href="/facts/Lipid/TdQR87HX">lipids</a>, including the remarkable carbon-carbon bond scission catalyzed by this enzyme. </p><p>The <i>CYP17A1</i> gene may also contain variants associated with increased risk of <a href="/facts/Coronary_artery_disease/szCt0nVx">coronary artery disease</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a>[<i>non-primary source needed</i>] </p> <h3>Protein</h3> <p>CYP17A1 is a 57.4 <a href="/facts/KDa/IMATU3vf">kDa</a> protein that belongs to the cytochrome P450 family.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The protein encoded by its cDNA is composed of 508 <a href="/facts/Amino_acid_residues/BptnTs9X">amino acid residues</a>. As an enzyme, CYP17A1 possesses an <a href="/facts/Active_site/u9ua7rGu">active site</a> that associates with a <a href="/facts/Heme/fRhyJAAb">heme</a> prosthetic group to catalyze biosynthetic reactions.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Based on its known structures while bound to two <a href="/facts/Steroidal/4AhMbgXt">steroidal</a> inhibitors, <a href="/facts/Abiraterone/GujVzHSy">abiraterone</a> and <a href="/facts/Galeterone/lfdEeIM3">galeterone</a>, CYP17A1 possesses the canonical cytochrome P450 fold present in other complex P450 enzymes that participate in <a href="/facts/Steroidogenesis/4AhMbgXt">steroidogenesis</a> or <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> metabolism, though it orients the steroid ligands toward the F and G helices, perpendicular to the heme group, rather than the β1 sheet.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="expression">Expression</h2> <p><a href="/facts/Gene_expression/alCPohLR">Expression</a> of CYP17A1 has been found in all of the traditional <a href="/facts/Steroidogenic/4AhMbgXt">steroidogenic</a> <a href="/facts/Tissue_(biology)/H7CpML7A">tissues</a> except the <a href="/facts/Placenta/7XUoks1b">placenta</a>, including the <a href="/facts/Zona_reticularis/a1wv59Hr">zona reticularis</a> and <a href="/facts/Zona_fasciculata/QGv1mbg8">zona fasciculata</a> of the <a href="/facts/Adrenal_cortex/t4EkJgdy">adrenal cortex</a>, the <a href="/facts/Leydig_cell/YEqlfy1d">Leydig cells</a> of the <a href="/facts/Testicle/Doy40hoq">testes</a>, the <a href="/facts/Thecal_cell/UaclmFyV">thecal cells</a> of the <a href="/facts/Ovary/z2hG6bNy">ovaries</a>, and, more recently, in <a href="/facts/Luteinization/R9rpFdKT">luteinized</a> <a href="/facts/Granulosa_cell/8KhMa9I3">granulosa cells</a> in <a href="/facts/Ovarian_follicle/7eKGUwb6">ovarian follicles</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> In addition to classical steroidogenic tissue, CYP17A1 has also been detected in the <a href="/facts/Heart/fF4KSGdk">heart</a>, <a href="/facts/Kidney/HBspPrv9">kidney</a>, and <a href="/facts/Adipose_tissue/PxxedB6e">adipose tissue</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> In the <a href="/facts/Fetus/evocHd0Y">fetus</a>, CYP17A1 has been reported in the kidney, <a href="/facts/Thymus/YYEJu7KA">thymus</a>, and <a href="/facts/Spleen/6NKn9d8s">spleen</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="function">Function</h2> <p>CYP17A1 is a member of the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> superfamily of enzymes localized in the <a href="/facts/Endoplasmic_reticulum/DVbLA7GE">endoplasmic reticulum</a>. Proteins in this family are monooxygenases that catalyze synthesis of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>, <a href="/facts/Steroid/4AhMbgXt">steroids</a> and other lipids and are involved in drug metabolism.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> CYP17A1 has both 17α-hydroxylase activity (<a href="/facts/Enzyme_Commission_number/Y5GNLRKX">EC</a> <a href="https://enzyme.expasy.org/EC/1.14.14.19">1.14.14.19</a>) and 17,20-lyase activity (<a href="/facts/Enzyme_Commission_number/Y5GNLRKX">EC</a> <a href="https://enzyme.expasy.org/EC/1.14.14.32">1.14.14.32</a>). The 17α-hydroxylase activity of CYP17A1 is required for the generation of <a href="/facts/Glucocorticoid/2P91Aj3S">glucocorticoids</a> such as cortisol, but both the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production of <a href="/facts/Androgen/Rxey0HxX">androgenic</a> and <a href="/facts/Oestrogenine/0kPqaIex">oestrogenic</a> sex steroids by converting <a href="/facts/17%25CE%25B1-hydroxypregnenolone/hSJrJMSB">17α-hydroxypregnenolone</a> to <a href="/facts/Dehydroepiandrosterone/djLk75uF">dehydroepiandrosterone (DHEA)</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Mutations in this gene are associated with isolated steroid-17α-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency, <a href="/facts/Pseudohermaphroditism/DyJs3v9V">pseudohermaphroditism</a>, and <a href="/facts/Congenital_adrenal_hyperplasia/HTXWkLl8">adrenal hyperplasia</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Furthermore, the 17,20-lyase activity is dependent on cytochrome <a href="/facts/Cytochrome_P450_reductase/vcsmawEh">P450 oxidoreductase</a> (POR) cytochrome b5 (CYB5) and <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Cytochrome b5 acts as a facilitator for 17,20 lyase activity of CYP17A1 and can donate a second electron to some P450s. In humans the production of <a href="/facts/Testosterone/uUumdhAz">testosterone</a> via pregnenolone to17-OHPreg and DHEA by the CYP17A1 requires POR.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> Human CYP17A1 protein is <a href="/facts/Protein_phosphorylation/4alcRDkM">phosphorylated</a> on serine and threonine residues by a <a href="/facts/CAMP-dependent_protein_kinase_A/kaKoYfbp">cAMP-dependent protein kinase</a>. Phosphorylation of the protein increases 17,20-lyase activity, while dephosphorylation virtually eliminates this activity.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p>Mutations in this gene are associated with rare forms of <a href="/facts/Congenital_adrenal_hyperplasia/HTXWkLl8">congenital adrenal hyperplasia</a>, specifically <a href="/facts/Congenital_adrenal_hyperplasia_due_to_17%25CE%25B1-hydroxylase_deficiency/Cn94f21p">17α-hydroxylase deficiency/17,20-lyase deficiency</a> and <a href="/facts/Isolated_17%2c20-lyase_deficiency/rvHwq3xf">isolated 17,20-lyase deficiency</a>.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p><p>In humans, the CYP17A1 gene is largely associated with endocrine effects and steroid hormone metabolism.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> Furthermore, mutations in the CYP17A1 gene are associated with rare forms of <a href="/facts/Congenital_adrenal_hyperplasia_due_to_17%25CE%25B1-hydroxylase_deficiency/Cn94f21p">congenital adrenal hyperplasia</a>, in particular 17α-hydroxylase deficiency/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Overall, CYP17A1 is an important target for inhibition in the treatment of prostate cancer because it produces androgen that is required for tumor cell growth.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> The decreased enzyme activity of CYP17A1 is related to infertility due to hypogonadotropic hypogonadism. In females, folliculogenesis is arrested, while in males, testicular atrophy with interstitial cell proliferation and arrested spermatogenesis. Although generally anovulatory, there are some case reports of women with 17α-hydroxylase deficiency who underwent spontaneous menarche with cyclic menses.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p> <p class="note">See also: <a href="/facts/Congenital_adrenal_hyperplasia_due_to_17%25CE%25B1-hydroxylase_deficiency/Cn94f21p">Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency</a></p> <h3>Clinical marker</h3> <p>A multi-locus genetic risk score study based on a combination of 27 loci, including the CYP17A1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p> <h2 id="as-a-drug-target">As a drug target</h2> <h3>CYP17A1 inhibitors</h3> <p class="note">Main article: <a href="/facts/CYP17A1_inhibitor/WsFbbhIz">CYP17A1 inhibitor</a></p> <p>In 2011, the FDA approved the CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold that is similar to the endogenous CYP17A1 substrates, with <a href="/facts/Prednisone/eGgPIauI">prednisone</a> for the treatment of <a href="/facts/Castration-resistant_prostate_cancer/Mx7XuDhm">castration-resistant prostate cancer</a>. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using <a href="/facts/Nonsteroidal/7TUS4VXE">nonsteroidal</a> scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> Potent inhibitors of the CYP17A1 enzyme provide a last line defense against ectopic androgenesis in advanced prostate cancer.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p><p>The drug <a href="/facts/Abiraterone_acetate/GujVzHSy">abiraterone acetate</a>, which is used to treat <a href="/facts/Castration-resistant_prostate_cancer/Mx7XuDhm">castration-resistant prostate cancer</a>, blocks the biosynthesis of androgens by inhibiting the CYP17A1 enzyme. Abiraterone acetate binds in the active site of the enzyme<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> and coordinates the <a href="/facts/Heme/fRhyJAAb">heme</a> iron through its pyridine nitrogen, mimicking the substrate.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p><p>Since 2014, <a href="/facts/Galeterone/lfdEeIM3">galeterone</a> has been in <a href="/facts/Phase_III_clinical_trials/o8hEodVu">phase III</a> <a href="/facts/Clinical_trial/q8LMr832">clinical trials</a> for <a href="/facts/Castration-resistant_prostate_cancer/Mx7XuDhm">castration-resistant prostate cancer</a>.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> </p><p><a href="/facts/Ketoconazole/UQcvnER5">Ketoconazole</a> is an older <a href="/facts/CYP17A1_inhibitor/WsFbbhIz">CYP17A1 inhibitor</a> that is now little used. However, ketoconazole competitively inhibits CYP17A1, therefore its effectiveness will depend on the concentration of ketoconazole. This is in contrast to the <a href="/facts/Abiraterone_acetate/GujVzHSy">abiraterone acetate</a>, that permanently (rather than competitively) disables CYP17A1, once it binds to it. </p><p><a href="/facts/Seviteronel/T6kzlqPU">Seviteronel</a> (VT-464) is a novel <a href="/facts/CYP17A1_inhibitor/WsFbbhIz">CYP17A1 inhibitor</a> which is aimed to avoid co-administration of glucocorticoid therapy.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> In the 2010s, it underwent various phases of clinical studies and preclinical models as a drug against prostate cancer or breast cancer.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p> <h2 id="steroidogenesis">Steroidogenesis</h2> <table><tbody><tr><td></td></tr></tbody></table> <h2 id="additional-images">Additional images</h2> <h2 id="see-also">See also</h2> <ul> <li>Biology portal</li></ul> <ul><li><a href="/facts/Steroidogenic_enzyme/zfzah2tq">Steroidogenic enzyme</a></li> <li><a href="/facts/Cytochrome_P450_oxidoreductase_deficiency/SRBwQtIG">Cytochrome P450 oxidoreductase deficiency</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Miura K, Yasuda K, Yanase T, Yamakita N, Sasano H, Nawata H, et al. (October 1996). <a href="https://doi.org/10.1210%2Fjcem.81.10.8855840">"Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: with a review of Japanese patients with mutations of CYP17"</a>. <i>The Journal of Clinical Endocrinology and Metabolism</i>. 81 (10): 3797–3801. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1210%2Fjcem.81.10.8855840">10.1210/jcem.81.10.8855840</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8855840">8855840</a>.</li> <li>Miller WL, Geller DH, Auchus RJ (1999). "The molecular basis of isolated 17,20 lyase deficiency". <i>Endocrine Research</i>. 24 (3–4): 817–825. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.3109%2F07435809809032692">10.3109/07435809809032692</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9888582">9888582</a>.</li> <li>Strauss JF (November 2003). "Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome". <i>Annals of the New York Academy of Sciences</i>. 997 (1): 42–48. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2003NYASA.997...42S">2003NYASA.997...42S</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1196%2Fannals.1290.005">10.1196/annals.1290.005</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14644808">14644808</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:23559461">23559461</a>.</li> <li>Haider SM, Patel JS, Poojari CS, Neidle S (July 2010). "Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy". <i>Journal of Molecular Biology</i>. 400 (5): 1078–1098. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.jmb.2010.05.069">10.1016/j.jmb.2010.05.069</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/20595043">20595043</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=CYP17A1+protein%2C+human">CYP17A1+protein,+human</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li>Human <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=CYP17A1"><i>CYP17A1</i></a> genome location and <a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=CYP17A1"><i>CYP17A1</i></a> gene details page in the <a href="/facts/UCSC_Genome_Browser/kwumPyLb">UCSC Genome Browser</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"CYP17A1 cytochrome P450 family 17 subfamily A member 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 2015-06-23. Retrieved 2016-09-27. <a href="https://www.ncbi.nlm.nih.gov/gene/1586" target="_blank">https://www.ncbi.nlm.nih.gov/gene/1586</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"BioGPS - your Gene Portal System". biogps.org. Archived from the original on 2011-08-20. Retrieved 2016-10-11. <a href="http://biogps.org/#goto=genereport&id=1586" target="_blank">http://biogps.org/#goto=genereport&id=1586</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Boulpaep EL, Boron, WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1180. ISBN 1-4160-2328-3. <a href="1-4160-2328-3" target="_blank">1-4160-2328-3</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Boulpaep EL, Boron, WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1180. ISBN 1-4160-2328-3. <a href="1-4160-2328-3" target="_blank">1-4160-2328-3</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>"CYP17A1 cytochrome P450 family 17 subfamily A member 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 2015-06-23. Retrieved 2016-09-27. <a href="https://www.ncbi.nlm.nih.gov/gene/1586" target="_blank">https://www.ncbi.nlm.nih.gov/gene/1586</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Vasaitis TS, Bruno RD, Njar VC (May 2011). "CYP17 inhibitors for prostate cancer therapy". The Journal of Steroid Biochemistry and Molecular Biology. 125 (1–2): 23–31. doi:10.1016/j.jsbmb.2010.11.005. PMC 3047603. PMID 21092758. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047603" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047603</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, et al. (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–2271. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608367" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608367</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>"CYP17A1 - Steroid 17-alpha-hydroxylase/17,20 lyase - Homo sapiens (Human) - CYP17A1 gene & protein". www.uniprot.org. Archived from the original on 2016-10-12. Retrieved 2016-10-11. <a href="https://www.uniprot.org/uniprot/P05093" target="_blank">https://www.uniprot.org/uniprot/P05093</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Estrada DF, Laurence JS, Scott EE (February 2016). "Cytochrome P450 17A1 Interactions with the FMN Domain of Its Reductase as Characterized by NMR". The Journal of Biological Chemistry. 291 (8): 3990–4003. doi:10.1074/jbc.M115.677294. PMC 4759177. PMID 26719338. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759177" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759177</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Vasaitis TS, Bruno RD, Njar VC (May 2011). "CYP17 inhibitors for prostate cancer therapy". The Journal of Steroid Biochemistry and Molecular Biology. 125 (1–2): 23–31. doi:10.1016/j.jsbmb.2010.11.005. PMC 3047603. 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