Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone
•UPC2-MS/MS show alternative pathway is dominant in PNT2 prostate cells.•11OHA4 metabolism in PNT2 cells is less efficient than in LNCaP cells.•11KDHT is efficiently glucuronidated in LNCaP cells while 11KT conjugation is poor.•In PCa tissue 11OHA4, 11KT, 11OHT and 11KDHT are present at significant...
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| creator | du Toit, Therina Bloem, Liezl M. Quanson, Jonathan L. Ehlers, Riaan Serafin, Antonio M. Swart, Amanda C. |
| description | •UPC2-MS/MS show alternative pathway is dominant in PNT2 prostate cells.•11OHA4 metabolism in PNT2 cells is less efficient than in LNCaP cells.•11KDHT is efficiently glucuronidated in LNCaP cells while 11KT conjugation is poor.•In PCa tissue 11OHA4, 11KT, 11OHT and 11KDHT are present at significant levels.•In PCa plasma 11OHA4, 11KT and 11KDHT are significantly higher than A4, T and DHT.
Adrenal C19 steroids serve as precursors to active androgens in the prostate. Androstenedione (A4), 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) are metabolised to potent androgen receptor (AR) agonists, dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The identification of 11OHA4 metabolites, 11KT and 11KDHT, as active androgens has placed a new perspective on adrenal C11-oxy C19 steroids and their contribution to prostate cancer (PCa).
We investigated adrenal androgen metabolism in normal epithelial prostate (PNT2) cells and in androgen-dependent prostate cancer (LNCaP) cells. We also analysed steroid profiles in PCa tissue and plasma, determining the presence of the C19 steroids and their derivatives using ultra-performance liquid chromatography (UHPLC)- and ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS).
In PNT2 cells, sixty percent A4 (60%) was primarily metabolised to 5α-androstanedione (5αDIONE) (40%), testosterone (T) (10%), and androsterone (AST) (10%). T (30%) was primarily metabolised to DHT (10%) while low levels of A4, 5αDIONE and 3αADIOL (≈20%) were detected. Conjugated steroids were not detected and downstream products were present at |
| doi_str_mv | 10.1016/j.jsbmb.2016.06.009 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1826703529</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960076016301819</els_id><sourcerecordid>1826703529</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1819-7c876740959e87649e12c3a2264b854d3e85999eff70fac3e1525dedf2ba600d3</originalsourceid><addsrcrecordid>eNp9Uc1OGzEQtqpWapryBL34yIENY2_2x0gcUARtJVCRgLPltcet011vsB1EXqsPUvWR6k040Eulkcbz833jmY-QTwwWDFh9ul6sYzd0C56DBWQD8YbMWNuIgnEOb8kMRA0FNDW8Jx9iXANAWbJmRv7chtG63vnvVJmAXvWUsd-_ih87E8bnnfLZxYQejRs90gGT6sbeJYzUebqZiioh1cprDFRj38cTmlyMW6QZTDe9ioM6ow-3K17c3J3e3NHHrfLJWadVypx0tP9MzMxpmhjyuJNc-YlpLF4n97QveeP2qNflj-SdVX3Eoxc_Jw9Xl_erL8X1t89fVxfXhWYtE0Wj26ZuliAqgfm1FMi4LhXn9bJrq6Upsa2EEGhtA1bpElnFK4PG8k7VAKack-MDb77B4zZ_QA4uTvsrj-M2StbyuoGy4iK3lodWnc8VA1q5CW5QYScZyEk_uZZ7_eSkn4RsMKHODyjMWzw5DDJqh_nMxgXUSZrR_Rf_F34Fq3Y</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1826703529</pqid></control><display><type>article</type><title>Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone</title><source>ScienceDirect Journals (5 years ago - present)</source><creator>du Toit, Therina ; Bloem, Liezl M. ; Quanson, Jonathan L. ; Ehlers, Riaan ; Serafin, Antonio M. ; Swart, Amanda C.</creator><creatorcontrib>du Toit, Therina ; Bloem, Liezl M. ; Quanson, Jonathan L. ; Ehlers, Riaan ; Serafin, Antonio M. ; Swart, Amanda C.</creatorcontrib><description>•UPC2-MS/MS show alternative pathway is dominant in PNT2 prostate cells.•11OHA4 metabolism in PNT2 cells is less efficient than in LNCaP cells.•11KDHT is efficiently glucuronidated in LNCaP cells while 11KT conjugation is poor.•In PCa tissue 11OHA4, 11KT, 11OHT and 11KDHT are present at significant levels.•In PCa plasma 11OHA4, 11KT and 11KDHT are significantly higher than A4, T and DHT.
Adrenal C19 steroids serve as precursors to active androgens in the prostate. Androstenedione (A4), 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) are metabolised to potent androgen receptor (AR) agonists, dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The identification of 11OHA4 metabolites, 11KT and 11KDHT, as active androgens has placed a new perspective on adrenal C11-oxy C19 steroids and their contribution to prostate cancer (PCa).
We investigated adrenal androgen metabolism in normal epithelial prostate (PNT2) cells and in androgen-dependent prostate cancer (LNCaP) cells. We also analysed steroid profiles in PCa tissue and plasma, determining the presence of the C19 steroids and their derivatives using ultra-performance liquid chromatography (UHPLC)- and ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS).
In PNT2 cells, sixty percent A4 (60%) was primarily metabolised to 5α-androstanedione (5αDIONE) (40%), testosterone (T) (10%), and androsterone (AST) (10%). T (30%) was primarily metabolised to DHT (10%) while low levels of A4, 5αDIONE and 3αADIOL (≈20%) were detected. Conjugated steroids were not detected and downstream products were present at <0.05μM. Only 20% of 11OHA4 and 11OHT were metabolised with the former yielding 11keto-androstenedione (11KA4), 11KDHT and 11β-hydroxy-5α-androstanedione (11OH-5αDIONE) and the latter yielding 11OHA4, 11KT and 11KDHT with downstream products <0.03μM. In LNCaP cells, A4 (90%) was metabolised to AST-glucuronide via the alternative pathway while T was detected as T-glucuronide with negligible conversion to downstream products. 11OHA4 (80%) and 11OHT (60%) were predominantly metabolised to 11KA4 and 11KT and in both assays more than 50% of 11KT was detected in the unconjugated form. In tissue, we detected C11-oxy C19 metabolites at significantly higher levels than the C19 steroids, with unconjugated 11KDHT, 11KT and 11OHA4 levels ranging between 13 and 37.5ng/g. Analyses of total steroid levels in plasma showed significant levels of 11OHA4 (≈230–440nM), 11KT (≈250–390nM) and 11KDHT (≈19nM). DHT levels (<0.14nM) were significantly lower.
In summary, 11β-hydroxysteroid dehydrogenase type 2 activity in PNT2 cells was substantially lower than in LNCaP cells, reflected in the conversion of 11OHA4 and 11OHT. Enzyme substrate preferences suggest that the alternate pathway is dominant in normal prostate cells. Glucuronidation activity was not detected in PNT2 cells and while all T derivatives were efficiently conjugated in LNCaP cells, 11KT was not. Substantial 11KT levels were also detected in both PCa tissue and plasma. 11OHA4 therefore presents a significant androgen precursor and its downstream metabolism to 11KT and 11KDHT as well as its presence in PCa tissue and plasma substantiate the importance of this adrenal androgen.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/j.jsbmb.2016.06.009</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><subject>11K-DHT ; 11keto-testosterone (11KT) ; Adrenal 11β -hydroxy-androstenedione (11β OHA4) ; Castration-resistant prostate cancer (CRPC) ; LC–MS/MS ; LNCaP prostate cancer cell model ; PNT2 epithelial prostate cell model</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 2017-02, Vol.166, p.54-67</ispartof><rights>2016 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1819-7c876740959e87649e12c3a2264b854d3e85999eff70fac3e1525dedf2ba600d3</citedby><cites>FETCH-LOGICAL-c1819-7c876740959e87649e12c3a2264b854d3e85999eff70fac3e1525dedf2ba600d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jsbmb.2016.06.009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids></links><search><creatorcontrib>du Toit, Therina</creatorcontrib><creatorcontrib>Bloem, Liezl M.</creatorcontrib><creatorcontrib>Quanson, Jonathan L.</creatorcontrib><creatorcontrib>Ehlers, Riaan</creatorcontrib><creatorcontrib>Serafin, Antonio M.</creatorcontrib><creatorcontrib>Swart, Amanda C.</creatorcontrib><title>Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone</title><title>The Journal of steroid biochemistry and molecular biology</title><description>•UPC2-MS/MS show alternative pathway is dominant in PNT2 prostate cells.•11OHA4 metabolism in PNT2 cells is less efficient than in LNCaP cells.•11KDHT is efficiently glucuronidated in LNCaP cells while 11KT conjugation is poor.•In PCa tissue 11OHA4, 11KT, 11OHT and 11KDHT are present at significant levels.•In PCa plasma 11OHA4, 11KT and 11KDHT are significantly higher than A4, T and DHT.
Adrenal C19 steroids serve as precursors to active androgens in the prostate. Androstenedione (A4), 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) are metabolised to potent androgen receptor (AR) agonists, dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The identification of 11OHA4 metabolites, 11KT and 11KDHT, as active androgens has placed a new perspective on adrenal C11-oxy C19 steroids and their contribution to prostate cancer (PCa).
We investigated adrenal androgen metabolism in normal epithelial prostate (PNT2) cells and in androgen-dependent prostate cancer (LNCaP) cells. We also analysed steroid profiles in PCa tissue and plasma, determining the presence of the C19 steroids and their derivatives using ultra-performance liquid chromatography (UHPLC)- and ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS).
In PNT2 cells, sixty percent A4 (60%) was primarily metabolised to 5α-androstanedione (5αDIONE) (40%), testosterone (T) (10%), and androsterone (AST) (10%). T (30%) was primarily metabolised to DHT (10%) while low levels of A4, 5αDIONE and 3αADIOL (≈20%) were detected. Conjugated steroids were not detected and downstream products were present at <0.05μM. Only 20% of 11OHA4 and 11OHT were metabolised with the former yielding 11keto-androstenedione (11KA4), 11KDHT and 11β-hydroxy-5α-androstanedione (11OH-5αDIONE) and the latter yielding 11OHA4, 11KT and 11KDHT with downstream products <0.03μM. In LNCaP cells, A4 (90%) was metabolised to AST-glucuronide via the alternative pathway while T was detected as T-glucuronide with negligible conversion to downstream products. 11OHA4 (80%) and 11OHT (60%) were predominantly metabolised to 11KA4 and 11KT and in both assays more than 50% of 11KT was detected in the unconjugated form. In tissue, we detected C11-oxy C19 metabolites at significantly higher levels than the C19 steroids, with unconjugated 11KDHT, 11KT and 11OHA4 levels ranging between 13 and 37.5ng/g. Analyses of total steroid levels in plasma showed significant levels of 11OHA4 (≈230–440nM), 11KT (≈250–390nM) and 11KDHT (≈19nM). DHT levels (<0.14nM) were significantly lower.
In summary, 11β-hydroxysteroid dehydrogenase type 2 activity in PNT2 cells was substantially lower than in LNCaP cells, reflected in the conversion of 11OHA4 and 11OHT. Enzyme substrate preferences suggest that the alternate pathway is dominant in normal prostate cells. Glucuronidation activity was not detected in PNT2 cells and while all T derivatives were efficiently conjugated in LNCaP cells, 11KT was not. Substantial 11KT levels were also detected in both PCa tissue and plasma. 11OHA4 therefore presents a significant androgen precursor and its downstream metabolism to 11KT and 11KDHT as well as its presence in PCa tissue and plasma substantiate the importance of this adrenal androgen.</description><subject>11K-DHT</subject><subject>11keto-testosterone (11KT)</subject><subject>Adrenal 11β -hydroxy-androstenedione (11β OHA4)</subject><subject>Castration-resistant prostate cancer (CRPC)</subject><subject>LC–MS/MS</subject><subject>LNCaP prostate cancer cell model</subject><subject>PNT2 epithelial prostate cell model</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9Uc1OGzEQtqpWapryBL34yIENY2_2x0gcUARtJVCRgLPltcet011vsB1EXqsPUvWR6k040Eulkcbz833jmY-QTwwWDFh9ul6sYzd0C56DBWQD8YbMWNuIgnEOb8kMRA0FNDW8Jx9iXANAWbJmRv7chtG63vnvVJmAXvWUsd-_ih87E8bnnfLZxYQejRs90gGT6sbeJYzUebqZiioh1cprDFRj38cTmlyMW6QZTDe9ioM6ow-3K17c3J3e3NHHrfLJWadVypx0tP9MzMxpmhjyuJNc-YlpLF4n97QveeP2qNflj-SdVX3Eoxc_Jw9Xl_erL8X1t89fVxfXhWYtE0Wj26ZuliAqgfm1FMi4LhXn9bJrq6Upsa2EEGhtA1bpElnFK4PG8k7VAKack-MDb77B4zZ_QA4uTvsrj-M2StbyuoGy4iK3lodWnc8VA1q5CW5QYScZyEk_uZZ7_eSkn4RsMKHODyjMWzw5DDJqh_nMxgXUSZrR_Rf_F34Fq3Y</recordid><startdate>201702</startdate><enddate>201702</enddate><creator>du Toit, Therina</creator><creator>Bloem, Liezl M.</creator><creator>Quanson, Jonathan L.</creator><creator>Ehlers, Riaan</creator><creator>Serafin, Antonio M.</creator><creator>Swart, Amanda C.</creator><general>Elsevier Ltd</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201702</creationdate><title>Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone</title><author>du Toit, Therina ; Bloem, Liezl M. ; Quanson, Jonathan L. ; Ehlers, Riaan ; Serafin, Antonio M. ; Swart, Amanda C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1819-7c876740959e87649e12c3a2264b854d3e85999eff70fac3e1525dedf2ba600d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>11K-DHT</topic><topic>11keto-testosterone (11KT)</topic><topic>Adrenal 11β -hydroxy-androstenedione (11β OHA4)</topic><topic>Castration-resistant prostate cancer (CRPC)</topic><topic>LC–MS/MS</topic><topic>LNCaP prostate cancer cell model</topic><topic>PNT2 epithelial prostate cell model</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>du Toit, Therina</creatorcontrib><creatorcontrib>Bloem, Liezl M.</creatorcontrib><creatorcontrib>Quanson, Jonathan L.</creatorcontrib><creatorcontrib>Ehlers, Riaan</creatorcontrib><creatorcontrib>Serafin, Antonio M.</creatorcontrib><creatorcontrib>Swart, Amanda C.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>du Toit, Therina</au><au>Bloem, Liezl M.</au><au>Quanson, Jonathan L.</au><au>Ehlers, Riaan</au><au>Serafin, Antonio M.</au><au>Swart, Amanda C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><date>2017-02</date><risdate>2017</risdate><volume>166</volume><spage>54</spage><epage>67</epage><pages>54-67</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>•UPC2-MS/MS show alternative pathway is dominant in PNT2 prostate cells.•11OHA4 metabolism in PNT2 cells is less efficient than in LNCaP cells.•11KDHT is efficiently glucuronidated in LNCaP cells while 11KT conjugation is poor.•In PCa tissue 11OHA4, 11KT, 11OHT and 11KDHT are present at significant levels.•In PCa plasma 11OHA4, 11KT and 11KDHT are significantly higher than A4, T and DHT.
Adrenal C19 steroids serve as precursors to active androgens in the prostate. Androstenedione (A4), 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) are metabolised to potent androgen receptor (AR) agonists, dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The identification of 11OHA4 metabolites, 11KT and 11KDHT, as active androgens has placed a new perspective on adrenal C11-oxy C19 steroids and their contribution to prostate cancer (PCa).
We investigated adrenal androgen metabolism in normal epithelial prostate (PNT2) cells and in androgen-dependent prostate cancer (LNCaP) cells. We also analysed steroid profiles in PCa tissue and plasma, determining the presence of the C19 steroids and their derivatives using ultra-performance liquid chromatography (UHPLC)- and ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS).
In PNT2 cells, sixty percent A4 (60%) was primarily metabolised to 5α-androstanedione (5αDIONE) (40%), testosterone (T) (10%), and androsterone (AST) (10%). T (30%) was primarily metabolised to DHT (10%) while low levels of A4, 5αDIONE and 3αADIOL (≈20%) were detected. Conjugated steroids were not detected and downstream products were present at <0.05μM. Only 20% of 11OHA4 and 11OHT were metabolised with the former yielding 11keto-androstenedione (11KA4), 11KDHT and 11β-hydroxy-5α-androstanedione (11OH-5αDIONE) and the latter yielding 11OHA4, 11KT and 11KDHT with downstream products <0.03μM. In LNCaP cells, A4 (90%) was metabolised to AST-glucuronide via the alternative pathway while T was detected as T-glucuronide with negligible conversion to downstream products. 11OHA4 (80%) and 11OHT (60%) were predominantly metabolised to 11KA4 and 11KT and in both assays more than 50% of 11KT was detected in the unconjugated form. In tissue, we detected C11-oxy C19 metabolites at significantly higher levels than the C19 steroids, with unconjugated 11KDHT, 11KT and 11OHA4 levels ranging between 13 and 37.5ng/g. Analyses of total steroid levels in plasma showed significant levels of 11OHA4 (≈230–440nM), 11KT (≈250–390nM) and 11KDHT (≈19nM). DHT levels (<0.14nM) were significantly lower.
In summary, 11β-hydroxysteroid dehydrogenase type 2 activity in PNT2 cells was substantially lower than in LNCaP cells, reflected in the conversion of 11OHA4 and 11OHT. Enzyme substrate preferences suggest that the alternate pathway is dominant in normal prostate cells. Glucuronidation activity was not detected in PNT2 cells and while all T derivatives were efficiently conjugated in LNCaP cells, 11KT was not. Substantial 11KT levels were also detected in both PCa tissue and plasma. 11OHA4 therefore presents a significant androgen precursor and its downstream metabolism to 11KT and 11KDHT as well as its presence in PCa tissue and plasma substantiate the importance of this adrenal androgen.</abstract><pub>Elsevier Ltd</pub><doi>10.1016/j.jsbmb.2016.06.009</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-0760 |
| ispartof | The Journal of steroid biochemistry and molecular biology, 2017-02, Vol.166, p.54-67 |
| issn | 0960-0760 1879-1220 |
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| source | ScienceDirect Journals (5 years ago - present) |
| subjects | 11K-DHT 11keto-testosterone (11KT) Adrenal 11β -hydroxy-androstenedione (11β OHA4) Castration-resistant prostate cancer (CRPC) LC–MS/MS LNCaP prostate cancer cell model PNT2 epithelial prostate cell model |
| title | Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone |
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