In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1
We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20‐hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3,1,20...
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creator | Slominski, Andrzej T. Kim, Tae‐Kang Shehabi, Haleem Z. Semak, Igor Tang, Edith K. Y. Nguyen, Minh N. Benson, Heather A. E. Korik, Elena Janjetovic, Zorica Chen, Jianjun Yates, Charles R. Postlethwaite, Arnold Li, Wei Tuckey, Robert C. |
description | We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20‐hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3,1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ~20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α‐hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)2D3 → 17,20,23(OH)3D3 with further 1α‐hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH)2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)2D3.—Slominski, A. T., Km, T.‐K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A., Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26, 3901–3915 (2012). www.fasebj.org |
doi_str_mv | 10.1096/fj.12-208975 |
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Y. ; Nguyen, Minh N. ; Benson, Heather A. E. ; Korik, Elena ; Janjetovic, Zorica ; Chen, Jianjun ; Yates, Charles R. ; Postlethwaite, Arnold ; Li, Wei ; Tuckey, Robert C.</creator><creatorcontrib>Slominski, Andrzej T. ; Kim, Tae‐Kang ; Shehabi, Haleem Z. ; Semak, Igor ; Tang, Edith K. Y. ; Nguyen, Minh N. ; Benson, Heather A. E. ; Korik, Elena ; Janjetovic, Zorica ; Chen, Jianjun ; Yates, Charles R. ; Postlethwaite, Arnold ; Li, Wei ; Tuckey, Robert C.</creatorcontrib><description>We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20‐hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3,1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ~20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α‐hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)2D3 → 17,20,23(OH)3D3 with further 1α‐hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH)2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)2D3.—Slominski, A. T., Km, T.‐K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A., Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26, 3901–3915 (2012). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.12-208975</identifier><identifier>PMID: 22683847</identifier><language>eng</language><publisher>Bethesda, MD, USA: Federation of American Societies for Experimental Biology</publisher><subject>20‐hydroxyvitamin D ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism ; adrenals ; Animals ; Cells, Cultured ; Cholecalciferol - metabolism ; Cholesterol Side-Chain Cleavage Enzyme - metabolism ; Chromatography, High Pressure Liquid ; CYP11A1 ; Female ; Humans ; keratinocytes ; Keratinocytes - enzymology ; Keratinocytes - metabolism ; placenta ; Polymerase Chain Reaction ; Rats ; Rats, Wistar ; Research Communications ; Tandem Mass Spectrometry</subject><ispartof>The FASEB journal, 2012-09, Vol.26 (9), p.3901-3915</ispartof><rights>FASEB</rights><rights>FASEB 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.12-208975$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.12-208975$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22683847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Slominski, Andrzej T.</creatorcontrib><creatorcontrib>Kim, Tae‐Kang</creatorcontrib><creatorcontrib>Shehabi, Haleem Z.</creatorcontrib><creatorcontrib>Semak, Igor</creatorcontrib><creatorcontrib>Tang, Edith K. Y.</creatorcontrib><creatorcontrib>Nguyen, Minh N.</creatorcontrib><creatorcontrib>Benson, Heather A. E.</creatorcontrib><creatorcontrib>Korik, Elena</creatorcontrib><creatorcontrib>Janjetovic, Zorica</creatorcontrib><creatorcontrib>Chen, Jianjun</creatorcontrib><creatorcontrib>Yates, Charles R.</creatorcontrib><creatorcontrib>Postlethwaite, Arnold</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Tuckey, Robert C.</creatorcontrib><title>In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20‐hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3,1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ~20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α‐hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)2D3 → 17,20,23(OH)3D3 with further 1α‐hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH)2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)2D3.—Slominski, A. T., Km, T.‐K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A., Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26, 3901–3915 (2012). www.fasebj.org</description><subject>20‐hydroxyvitamin D</subject><subject>25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism</subject><subject>adrenals</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Cholecalciferol - metabolism</subject><subject>Cholesterol Side-Chain Cleavage Enzyme - metabolism</subject><subject>Chromatography, High Pressure Liquid</subject><subject>CYP11A1</subject><subject>Female</subject><subject>Humans</subject><subject>keratinocytes</subject><subject>Keratinocytes - enzymology</subject><subject>Keratinocytes - metabolism</subject><subject>placenta</subject><subject>Polymerase Chain Reaction</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Research Communications</subject><subject>Tandem Mass Spectrometry</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFv1DAQhS0Eokvhxhn5yCXteJzYzgWJbimtVIlKwIGT5bXH1KvEXpJsqv33BG2p4DTSe5_e08ww9lbAmYBWncftmcAKwbS6ecZWopFQKaPgOVstGlZKSXPCXo3jFgAECPWSnSAqI02tV2x7k_mc5sJpToGyJx7LwB3PZaaO79x0_-AOvMQFmlyfMr-UvKfJbUqXxp6nnKbkJgp8c-B3dQOj99zlwPsSUkxHff3jDvWFeM1eRNeN9OZxnrLvV5--ra-r2y-fb9Yfb6sdYgtVjaHWEoXQgkJNUjoNLQGiJoMI2tVNgz6GYGT0GlAtqPdShwhGt0TylH045u72m56CpzwNrrO7IfVuONjikv3fyene_iyzlTU2S8US8P4xYCi_9jROtk-jp65zmcp-tAKkVo0SplnQd_92PZX8PfAC6CPwkDo6PPkC7J_n2bi1Au3xefbq6wUu-wC0IEH-Bp8Si8w</recordid><startdate>201209</startdate><enddate>201209</enddate><creator>Slominski, Andrzej T.</creator><creator>Kim, Tae‐Kang</creator><creator>Shehabi, Haleem Z.</creator><creator>Semak, Igor</creator><creator>Tang, Edith K. Y.</creator><creator>Nguyen, Minh N.</creator><creator>Benson, Heather A. E.</creator><creator>Korik, Elena</creator><creator>Janjetovic, Zorica</creator><creator>Chen, Jianjun</creator><creator>Yates, Charles R.</creator><creator>Postlethwaite, Arnold</creator><creator>Li, Wei</creator><creator>Tuckey, Robert C.</creator><general>Federation of American Societies for Experimental Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201209</creationdate><title>In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1</title><author>Slominski, Andrzej T. ; Kim, Tae‐Kang ; Shehabi, Haleem Z. ; Semak, Igor ; Tang, Edith K. Y. ; Nguyen, Minh N. ; Benson, Heather A. E. ; Korik, Elena ; Janjetovic, Zorica ; Chen, Jianjun ; Yates, Charles R. ; Postlethwaite, Arnold ; Li, Wei ; Tuckey, Robert C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2290-42d47321171ed4e33a709e0227e82207a4552cfdd83fc7026211cc37df0879ee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>20‐hydroxyvitamin D</topic><topic>25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism</topic><topic>adrenals</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Cholecalciferol - metabolism</topic><topic>Cholesterol Side-Chain Cleavage Enzyme - metabolism</topic><topic>Chromatography, High Pressure Liquid</topic><topic>CYP11A1</topic><topic>Female</topic><topic>Humans</topic><topic>keratinocytes</topic><topic>Keratinocytes - enzymology</topic><topic>Keratinocytes - metabolism</topic><topic>placenta</topic><topic>Polymerase Chain Reaction</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Research Communications</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Slominski, Andrzej T.</creatorcontrib><creatorcontrib>Kim, Tae‐Kang</creatorcontrib><creatorcontrib>Shehabi, Haleem Z.</creatorcontrib><creatorcontrib>Semak, Igor</creatorcontrib><creatorcontrib>Tang, Edith K. Y.</creatorcontrib><creatorcontrib>Nguyen, Minh N.</creatorcontrib><creatorcontrib>Benson, Heather A. E.</creatorcontrib><creatorcontrib>Korik, Elena</creatorcontrib><creatorcontrib>Janjetovic, Zorica</creatorcontrib><creatorcontrib>Chen, Jianjun</creatorcontrib><creatorcontrib>Yates, Charles R.</creatorcontrib><creatorcontrib>Postlethwaite, Arnold</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Tuckey, Robert C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Slominski, Andrzej T.</au><au>Kim, Tae‐Kang</au><au>Shehabi, Haleem Z.</au><au>Semak, Igor</au><au>Tang, Edith K. Y.</au><au>Nguyen, Minh N.</au><au>Benson, Heather A. E.</au><au>Korik, Elena</au><au>Janjetovic, Zorica</au><au>Chen, Jianjun</au><au>Yates, Charles R.</au><au>Postlethwaite, Arnold</au><au>Li, Wei</au><au>Tuckey, Robert C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2012-09</date><risdate>2012</risdate><volume>26</volume><issue>9</issue><spage>3901</spage><epage>3915</epage><pages>3901-3915</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20‐hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3,1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ~20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α‐hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)2D3 → 17,20,23(OH)3D3 with further 1α‐hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH)2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)2D3.—Slominski, A. T., Km, T.‐K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A., Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26, 3901–3915 (2012). www.fasebj.org</abstract><cop>Bethesda, MD, USA</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>22683847</pmid><doi>10.1096/fj.12-208975</doi><tpages>15</tpages></addata></record> |
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subjects | 20‐hydroxyvitamin D 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism adrenals Animals Cells, Cultured Cholecalciferol - metabolism Cholesterol Side-Chain Cleavage Enzyme - metabolism Chromatography, High Pressure Liquid CYP11A1 Female Humans keratinocytes Keratinocytes - enzymology Keratinocytes - metabolism placenta Polymerase Chain Reaction Rats Rats, Wistar Research Communications Tandem Mass Spectrometry |
title | In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1 |
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