{"title":"7-半胱氨酸-吡咯偶联物:一种新的潜在的吡咯利西啶生物碱DNA反应代谢物","authors":"Xiaobo He, Q. Xia, Liang Ma, P. Fu","doi":"10.1080/10590501.2015.1135593","DOIUrl":null,"url":null,"abstract":"ABSTRACT Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.","PeriodicalId":53200,"journal":{"name":"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis","volume":"34 1","pages":"57 - 76"},"PeriodicalIF":1.2000,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/10590501.2015.1135593","citationCount":"26","resultStr":"{\"title\":\"7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids\",\"authors\":\"Xiaobo He, Q. Xia, Liang Ma, P. Fu\",\"doi\":\"10.1080/10590501.2015.1135593\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"ABSTRACT Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.\",\"PeriodicalId\":53200,\"journal\":{\"name\":\"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis\",\"volume\":\"34 1\",\"pages\":\"57 - 76\"},\"PeriodicalIF\":1.2000,\"publicationDate\":\"2016-01-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1080/10590501.2015.1135593\",\"citationCount\":\"26\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis\",\"FirstCategoryId\":\"93\",\"ListUrlMain\":\"https://doi.org/10.1080/10590501.2015.1135593\",\"RegionNum\":4,\"RegionCategory\":\"环境科学与生态学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"ENVIRONMENTAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1080/10590501.2015.1135593","RegionNum":4,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}
7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids
ABSTRACT Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.
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