Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites
Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function...
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| description | Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis. |
| doi_str_mv | 10.1371/journal.pone.0132151 |
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Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0132151</identifier><identifier>PMID: 26317351</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3T3 Cells ; Accumulation ; Acetylcysteine ; Acetylcysteine - metabolism ; Acids ; Adipogenesis ; Adipogenesis - drug effects ; Administration, Oral ; Animals ; Anticancer properties ; Antitumor agents ; Apoptosis ; Biological activity ; Biomarkers ; Biotechnology ; Bladder ; Bladder cancer ; Cancer ; Cell cycle ; DNA methylation ; Epigenetics ; Food ; Gene Expression Regulation - drug effects ; Glutathione - metabolism ; Hepatocytes ; Isothiocyanate ; Isothiocyanates - administration & dosage ; Isothiocyanates - pharmacokinetics ; Isothiocyanates - urine ; Kinases ; Lipid Metabolism - drug effects ; Lipids ; Lipogenesis ; Lipogenesis - drug effects ; Liver ; Male ; Metabolism ; Metabolites ; Mice ; Mustard ; Obesity ; Oleic acid ; Oleic Acid - pharmacology ; Oral administration ; Organs ; Peroxisome proliferator-activated receptors ; Pharmacokinetics ; Pharmacology ; Phytochemicals ; Preadipocytes ; Rats ; Rodents ; Studies ; Tissue analysis ; Tissue Distribution ; Urine ; Vegetables</subject><ispartof>PloS one, 2015-08, Vol.10 (8), p.e0132151-e0132151</ispartof><rights>2015 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Kim et al 2015 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-415c0e9d1b56988f99f6a4f49297e2ebd618630e9d4c18b2ed7f5afeb6c0f6f13</citedby><cites>FETCH-LOGICAL-c592t-415c0e9d1b56988f99f6a4f49297e2ebd618630e9d4c18b2ed7f5afeb6c0f6f13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552636/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552636/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26317351$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Alisi, Anna</contributor><creatorcontrib>Kim, Yang-Ji</creatorcontrib><creatorcontrib>Lee, Da-Hye</creatorcontrib><creatorcontrib>Ahn, Jiyun</creatorcontrib><creatorcontrib>Chung, Woo-Jae</creatorcontrib><creatorcontrib>Jang, Young Jin</creatorcontrib><creatorcontrib>Seong, Ki-Seung</creatorcontrib><creatorcontrib>Moon, Jae-Hak</creatorcontrib><creatorcontrib>Ha, Tae Youl</creatorcontrib><creatorcontrib>Jung, Chang Hwa</creatorcontrib><title>Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.</description><subject>3T3 Cells</subject><subject>Accumulation</subject><subject>Acetylcysteine</subject><subject>Acetylcysteine - metabolism</subject><subject>Acids</subject><subject>Adipogenesis</subject><subject>Adipogenesis - drug effects</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Biological activity</subject><subject>Biomarkers</subject><subject>Biotechnology</subject><subject>Bladder</subject><subject>Bladder cancer</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>DNA methylation</subject><subject>Epigenetics</subject><subject>Food</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Glutathione - metabolism</subject><subject>Hepatocytes</subject><subject>Isothiocyanate</subject><subject>Isothiocyanates - administration & dosage</subject><subject>Isothiocyanates - pharmacokinetics</subject><subject>Isothiocyanates - urine</subject><subject>Kinases</subject><subject>Lipid Metabolism - drug effects</subject><subject>Lipids</subject><subject>Lipogenesis</subject><subject>Lipogenesis - drug effects</subject><subject>Liver</subject><subject>Male</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mustard</subject><subject>Obesity</subject><subject>Oleic acid</subject><subject>Oleic Acid - pharmacology</subject><subject>Oral administration</subject><subject>Organs</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Phytochemicals</subject><subject>Preadipocytes</subject><subject>Rats</subject><subject>Rodents</subject><subject>Studies</subject><subject>Tissue analysis</subject><subject>Tissue Distribution</subject><subject>Urine</subject><subject>Vegetables</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptkl2PEyEUhidG437oPzA6iTd7sdOFYYDhxqRZV21SoxfrNWGYQ0ulUIEx6b93aqebXeMVJ_Cc93zwFsUbjGaYcHyzCUP0ys12wcMMYVJjip8V51iQumI1Is8fxWfFRUobhChpGXtZnNWMYE4oPi9239cqbpUOP62HbHW6Lu9tSgOUH23K0XZDtsFfl8r35dxnWy3tLqzAW30z709heWcM6JzKYMq5c3tXLVLIaxv0XnmVofwKWXXB2QzpVfHCKJfg9XReFj8-3d3ffqmW3z4vbufLSlNR56rBVCMQPe4oE21rhDBMNaYRteBQQ9cz3DJyIBqN266GnhuqDHRMI8MMJpfFu6PuzoUkp2UliTlqKeMtoyOxOBJ9UBu5i3ar4l4GZeXfixBXUsVxJQ4k04Tzrhe649BQrQWldFSAum9p21M-an2Yqg3dFnoNPkflnog-ffF2LVfht2woHT-DjQJXk0AMvwZIWW5t0uCc8hCGY98CIYzRiL7_B_3_dM2R0jGkFME8NIORPBjolCUPBpKTgca0t48HeUg6OYb8AeCvxec</recordid><startdate>20150828</startdate><enddate>20150828</enddate><creator>Kim, Yang-Ji</creator><creator>Lee, Da-Hye</creator><creator>Ahn, Jiyun</creator><creator>Chung, Woo-Jae</creator><creator>Jang, Young Jin</creator><creator>Seong, Ki-Seung</creator><creator>Moon, Jae-Hak</creator><creator>Ha, Tae Youl</creator><creator>Jung, Chang Hwa</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150828</creationdate><title>Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites</title><author>Kim, Yang-Ji ; Lee, Da-Hye ; Ahn, Jiyun ; Chung, Woo-Jae ; Jang, Young Jin ; Seong, Ki-Seung ; Moon, Jae-Hak ; Ha, Tae Youl ; Jung, Chang Hwa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-415c0e9d1b56988f99f6a4f49297e2ebd618630e9d4c18b2ed7f5afeb6c0f6f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3T3 Cells</topic><topic>Accumulation</topic><topic>Acetylcysteine</topic><topic>Acetylcysteine - metabolism</topic><topic>Acids</topic><topic>Adipogenesis</topic><topic>Adipogenesis - drug effects</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antitumor agents</topic><topic>Apoptosis</topic><topic>Biological activity</topic><topic>Biomarkers</topic><topic>Biotechnology</topic><topic>Bladder</topic><topic>Bladder cancer</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>DNA methylation</topic><topic>Epigenetics</topic><topic>Food</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Glutathione - metabolism</topic><topic>Hepatocytes</topic><topic>Isothiocyanate</topic><topic>Isothiocyanates - administration & dosage</topic><topic>Isothiocyanates - pharmacokinetics</topic><topic>Isothiocyanates - urine</topic><topic>Kinases</topic><topic>Lipid Metabolism - drug effects</topic><topic>Lipids</topic><topic>Lipogenesis</topic><topic>Lipogenesis - drug effects</topic><topic>Liver</topic><topic>Male</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Mustard</topic><topic>Obesity</topic><topic>Oleic acid</topic><topic>Oleic Acid - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Yang-Ji</au><au>Lee, Da-Hye</au><au>Ahn, Jiyun</au><au>Chung, Woo-Jae</au><au>Jang, Young Jin</au><au>Seong, Ki-Seung</au><au>Moon, Jae-Hak</au><au>Ha, Tae Youl</au><au>Jung, Chang Hwa</au><au>Alisi, Anna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-08-28</date><risdate>2015</risdate><volume>10</volume><issue>8</issue><spage>e0132151</spage><epage>e0132151</epage><pages>e0132151-e0132151</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26317351</pmid><doi>10.1371/journal.pone.0132151</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-08, Vol.10 (8), p.e0132151-e0132151 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1708567865 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3T3 Cells Accumulation Acetylcysteine Acetylcysteine - metabolism Acids Adipogenesis Adipogenesis - drug effects Administration, Oral Animals Anticancer properties Antitumor agents Apoptosis Biological activity Biomarkers Biotechnology Bladder Bladder cancer Cancer Cell cycle DNA methylation Epigenetics Food Gene Expression Regulation - drug effects Glutathione - metabolism Hepatocytes Isothiocyanate Isothiocyanates - administration & dosage Isothiocyanates - pharmacokinetics Isothiocyanates - urine Kinases Lipid Metabolism - drug effects Lipids Lipogenesis Lipogenesis - drug effects Liver Male Metabolism Metabolites Mice Mustard Obesity Oleic acid Oleic Acid - pharmacology Oral administration Organs Peroxisome proliferator-activated receptors Pharmacokinetics Pharmacology Phytochemicals Preadipocytes Rats Rodents Studies Tissue analysis Tissue Distribution Urine Vegetables |
| title | Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T16%3A20%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pharmacokinetics,%20Tissue%20Distribution,%20and%20Anti-Lipogenic/Adipogenic%20Effects%20of%20Allyl-Isothiocyanate%20Metabolites&rft.jtitle=PloS%20one&rft.au=Kim,%20Yang-Ji&rft.date=2015-08-28&rft.volume=10&rft.issue=8&rft.spage=e0132151&rft.epage=e0132151&rft.pages=e0132151-e0132151&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0132151&rft_dat=%3Cproquest_plos_%3E1708900110%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1708567865&rft_id=info:pmid/26317351&rft_doaj_id=oai_doaj_org_article_6c377bd9cb7e45cc9555653e2d858d57&rfr_iscdi=true |