Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases
Safrole (SFL) is an IARC class 2B carcinogen. To better understand the mechanism involved in SFL toxicity, we explored the potential interactions between SFL metabolites and RNA. Three guanosine adducts (G1-G3), two adenosine adducts (A1-A2), and two cytosine adducts (C1–C2) were detected by LC-MS/M...
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| Veröffentlicht in: | Food and chemical toxicology 2023-04, Vol.174, p.113688-113688, Article 113688 |
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| container_title | Food and chemical toxicology |
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| creator | Wang, Xin Ran, Guangyun Liao, Yufen Gong, Bowen Wu, Chutian Tan, Rong Liu, Ying Zhang, Shiyu Peng, Ying Li, Weiwei Zheng, Jiang |
| description | Safrole (SFL) is an IARC class 2B carcinogen. To better understand the mechanism involved in SFL toxicity, we explored the potential interactions between SFL metabolites and RNA. Three guanosine adducts (G1-G3), two adenosine adducts (A1-A2), and two cytosine adducts (C1–C2) were detected by LC-MS/MS in mouse liver S9 incubations, cultured mouse primary hepatocytes, and liver tissues of mice after exposure to SFL. These adducts were chemically synthesized, and one of the guanosine adducts was structurally characterized by 1H-NMR. Studies in vitro and in vivo showed that SFL was oxidized by cytochrome P450 enzymes to the corresponding 1′-hydroxyl metabolite which was further metabolized by sulfotransferases to form allylic sulfate esters. The formed reactive intermediate(s) subsequently reacted with bases of RNA, leading to RNA adduction, which could play a partial role in the toxicities of SFL through the alteration of RNA biochemical properties and interruption of RNA functions.
[Display omitted]
•MetaBolic activation of safrole resulted in the formation of a carbocation intermediate which modified RNA.•An adducted guanosine was chemically synthesized and characterized by mass spectrometry and nuclear magnetic resonance.•The observed RNA adduction is mediated by cytochrome P450 enzymes and sulfotransferases. |
| doi_str_mv | 10.1016/j.fct.2023.113688 |
| format | Article |
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[Display omitted]
•MetaBolic activation of safrole resulted in the formation of a carbocation intermediate which modified RNA.•An adducted guanosine was chemically synthesized and characterized by mass spectrometry and nuclear magnetic resonance.•The observed RNA adduction is mediated by cytochrome P450 enzymes and sulfotransferases.</description><identifier>ISSN: 0278-6915</identifier><identifier>EISSN: 1873-6351</identifier><identifier>DOI: 10.1016/j.fct.2023.113688</identifier><identifier>PMID: 36841326</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Activation, Metabolic ; adenosine ; Animals ; carcinogens ; Chromatography, Liquid ; class ; cytochrome P-450 ; Cytochrome P-450 Enzyme System - metabolism ; cytosine ; DNA Adducts ; guanosine ; hepatocytes ; ingredients ; LC−MS/MS ; liver ; Metabolic activation ; metabolites ; Mice ; RNA ; RNA - metabolism ; RNA adduction ; Safrole ; Spices ; sulfates ; sulfotransferases ; Sulfotransferases - metabolism ; Tandem Mass Spectrometry ; toxicity</subject><ispartof>Food and chemical toxicology, 2023-04, Vol.174, p.113688-113688, Article 113688</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-98547e7c8a7f6b12fe85f71476fa4c4ba1497540ae32ecd77d56c6ff4d51b9753</citedby><cites>FETCH-LOGICAL-c386t-98547e7c8a7f6b12fe85f71476fa4c4ba1497540ae32ecd77d56c6ff4d51b9753</cites><orcidid>0000-0002-8187-2147</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S027869152300090X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36841326$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Xin</creatorcontrib><creatorcontrib>Ran, Guangyun</creatorcontrib><creatorcontrib>Liao, Yufen</creatorcontrib><creatorcontrib>Gong, Bowen</creatorcontrib><creatorcontrib>Wu, Chutian</creatorcontrib><creatorcontrib>Tan, Rong</creatorcontrib><creatorcontrib>Liu, Ying</creatorcontrib><creatorcontrib>Zhang, Shiyu</creatorcontrib><creatorcontrib>Peng, Ying</creatorcontrib><creatorcontrib>Li, Weiwei</creatorcontrib><creatorcontrib>Zheng, Jiang</creatorcontrib><title>Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases</title><title>Food and chemical toxicology</title><addtitle>Food Chem Toxicol</addtitle><description>Safrole (SFL) is an IARC class 2B carcinogen. To better understand the mechanism involved in SFL toxicity, we explored the potential interactions between SFL metabolites and RNA. Three guanosine adducts (G1-G3), two adenosine adducts (A1-A2), and two cytosine adducts (C1–C2) were detected by LC-MS/MS in mouse liver S9 incubations, cultured mouse primary hepatocytes, and liver tissues of mice after exposure to SFL. These adducts were chemically synthesized, and one of the guanosine adducts was structurally characterized by 1H-NMR. Studies in vitro and in vivo showed that SFL was oxidized by cytochrome P450 enzymes to the corresponding 1′-hydroxyl metabolite which was further metabolized by sulfotransferases to form allylic sulfate esters. The formed reactive intermediate(s) subsequently reacted with bases of RNA, leading to RNA adduction, which could play a partial role in the toxicities of SFL through the alteration of RNA biochemical properties and interruption of RNA functions.
[Display omitted]
•MetaBolic activation of safrole resulted in the formation of a carbocation intermediate which modified RNA.•An adducted guanosine was chemically synthesized and characterized by mass spectrometry and nuclear magnetic resonance.•The observed RNA adduction is mediated by cytochrome P450 enzymes and sulfotransferases.</description><subject>Activation, Metabolic</subject><subject>adenosine</subject><subject>Animals</subject><subject>carcinogens</subject><subject>Chromatography, Liquid</subject><subject>class</subject><subject>cytochrome P-450</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>cytosine</subject><subject>DNA Adducts</subject><subject>guanosine</subject><subject>hepatocytes</subject><subject>ingredients</subject><subject>LC−MS/MS</subject><subject>liver</subject><subject>Metabolic activation</subject><subject>metabolites</subject><subject>Mice</subject><subject>RNA</subject><subject>RNA - metabolism</subject><subject>RNA adduction</subject><subject>Safrole</subject><subject>Spices</subject><subject>sulfates</subject><subject>sulfotransferases</subject><subject>Sulfotransferases - metabolism</subject><subject>Tandem Mass Spectrometry</subject><subject>toxicity</subject><issn>0278-6915</issn><issn>1873-6351</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1uFDEUhS0EIpvAA9AglzSz-N9eUUURIUgRIAS15bGvkVcz48X2RFpegNfG0YaUUN3ifucU50PoFSVbSqh6u99G37aMML6llCtjnqANNZoPikv6FG0I02ZQOyrP0Hmte0KIplo9R2edFZQztUG_r3OZXUt5wTnir58usQth9a3iAnWdWlp-4FjyjGdobsxT8tj5lu4eI_WQPOCOFQgJloar6_wEPRCSaxDweMRfhCQYll_HGSp2S8C9OuZW3FIjFFehvkDPopsqvHy4F-j79ftvVzfD7ecPH68ubwfPjWrDzkihQXvjdFQjZRGMjJoKraITXoyOip2WgjjgDHzQOkjlVYwiSDr2D79Ab069h5J_rlCbnVP1ME1ugbxWywwXTEpC2f9RbQgxjFPdUXpCfcm1Foj2UNLsytFSYu9V2b3tquy9KntS1TOvH-rXsW_1mPjrpgPvTgD0Pe4SFFt9X9j3XQv0spDTP-r_AD-Opac</recordid><startdate>202304</startdate><enddate>202304</enddate><creator>Wang, Xin</creator><creator>Ran, Guangyun</creator><creator>Liao, Yufen</creator><creator>Gong, Bowen</creator><creator>Wu, Chutian</creator><creator>Tan, Rong</creator><creator>Liu, Ying</creator><creator>Zhang, Shiyu</creator><creator>Peng, Ying</creator><creator>Li, Weiwei</creator><creator>Zheng, Jiang</creator><general>Elsevier Ltd</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>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0002-8187-2147</orcidid></search><sort><creationdate>202304</creationdate><title>Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases</title><author>Wang, Xin ; Ran, Guangyun ; Liao, Yufen ; Gong, Bowen ; Wu, Chutian ; Tan, Rong ; Liu, Ying ; Zhang, Shiyu ; Peng, Ying ; Li, Weiwei ; Zheng, Jiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-98547e7c8a7f6b12fe85f71476fa4c4ba1497540ae32ecd77d56c6ff4d51b9753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Activation, Metabolic</topic><topic>adenosine</topic><topic>Animals</topic><topic>carcinogens</topic><topic>Chromatography, Liquid</topic><topic>class</topic><topic>cytochrome P-450</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>cytosine</topic><topic>DNA Adducts</topic><topic>guanosine</topic><topic>hepatocytes</topic><topic>ingredients</topic><topic>LC−MS/MS</topic><topic>liver</topic><topic>Metabolic activation</topic><topic>metabolites</topic><topic>Mice</topic><topic>RNA</topic><topic>RNA - metabolism</topic><topic>RNA adduction</topic><topic>Safrole</topic><topic>Spices</topic><topic>sulfates</topic><topic>sulfotransferases</topic><topic>Sulfotransferases - metabolism</topic><topic>Tandem Mass Spectrometry</topic><topic>toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Xin</creatorcontrib><creatorcontrib>Ran, Guangyun</creatorcontrib><creatorcontrib>Liao, Yufen</creatorcontrib><creatorcontrib>Gong, Bowen</creatorcontrib><creatorcontrib>Wu, Chutian</creatorcontrib><creatorcontrib>Tan, Rong</creatorcontrib><creatorcontrib>Liu, Ying</creatorcontrib><creatorcontrib>Zhang, Shiyu</creatorcontrib><creatorcontrib>Peng, Ying</creatorcontrib><creatorcontrib>Li, Weiwei</creatorcontrib><creatorcontrib>Zheng, Jiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Food and chemical toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Xin</au><au>Ran, Guangyun</au><au>Liao, Yufen</au><au>Gong, Bowen</au><au>Wu, Chutian</au><au>Tan, Rong</au><au>Liu, Ying</au><au>Zhang, Shiyu</au><au>Peng, Ying</au><au>Li, Weiwei</au><au>Zheng, Jiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases</atitle><jtitle>Food and chemical toxicology</jtitle><addtitle>Food Chem Toxicol</addtitle><date>2023-04</date><risdate>2023</risdate><volume>174</volume><spage>113688</spage><epage>113688</epage><pages>113688-113688</pages><artnum>113688</artnum><issn>0278-6915</issn><eissn>1873-6351</eissn><abstract>Safrole (SFL) is an IARC class 2B carcinogen. To better understand the mechanism involved in SFL toxicity, we explored the potential interactions between SFL metabolites and RNA. Three guanosine adducts (G1-G3), two adenosine adducts (A1-A2), and two cytosine adducts (C1–C2) were detected by LC-MS/MS in mouse liver S9 incubations, cultured mouse primary hepatocytes, and liver tissues of mice after exposure to SFL. These adducts were chemically synthesized, and one of the guanosine adducts was structurally characterized by 1H-NMR. Studies in vitro and in vivo showed that SFL was oxidized by cytochrome P450 enzymes to the corresponding 1′-hydroxyl metabolite which was further metabolized by sulfotransferases to form allylic sulfate esters. The formed reactive intermediate(s) subsequently reacted with bases of RNA, leading to RNA adduction, which could play a partial role in the toxicities of SFL through the alteration of RNA biochemical properties and interruption of RNA functions.
[Display omitted]
•MetaBolic activation of safrole resulted in the formation of a carbocation intermediate which modified RNA.•An adducted guanosine was chemically synthesized and characterized by mass spectrometry and nuclear magnetic resonance.•The observed RNA adduction is mediated by cytochrome P450 enzymes and sulfotransferases.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>36841326</pmid><doi>10.1016/j.fct.2023.113688</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8187-2147</orcidid></addata></record> |
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| ispartof | Food and chemical toxicology, 2023-04, Vol.174, p.113688-113688, Article 113688 |
| issn | 0278-6915 1873-6351 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Activation, Metabolic adenosine Animals carcinogens Chromatography, Liquid class cytochrome P-450 Cytochrome P-450 Enzyme System - metabolism cytosine DNA Adducts guanosine hepatocytes ingredients LC−MS/MS liver Metabolic activation metabolites Mice RNA RNA - metabolism RNA adduction Safrole Spices sulfates sulfotransferases Sulfotransferases - metabolism Tandem Mass Spectrometry toxicity |
| title | Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases |
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