Catechol Estrogen 4-Hydroxyequilenin Is a Substrate and an Inhibitor of Catechol-O-Methyltransferase
DC Field | Value | Language |
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dc.contributor.author | Yao, JQ | - |
dc.contributor.author | Li, Y | - |
dc.contributor.author | Chang, Min Sun | - |
dc.contributor.author | Wu, HP | - |
dc.contributor.author | Yang, XF | - |
dc.contributor.author | Goodman, JE | - |
dc.contributor.author | Liu, XM | - |
dc.contributor.author | Liu, H | - |
dc.contributor.author | Mesecar, AD | - |
dc.contributor.author | van Breemen, RB | - |
dc.contributor.author | Yager, JD | - |
dc.contributor.author | Bolton, JL | - |
dc.date.accessioned | 2022-04-19T12:04:45Z | - |
dc.date.available | 2022-04-19T12:04:45Z | - |
dc.date.issued | 2003-05 | - |
dc.identifier.issn | 0893-228X | - |
dc.identifier.uri | https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/149165 | - |
dc.description.abstract | Redox and/or electrophilic metabolites formed during estrogen metabolism may play a role in estrogen carcinogenesis. 4-Hydroxyequilenin (4-OHEN) is the major phase I catechol metabolite of the equine estrogens equilenin and equilin, which are components of the most widely prescribed estrogen replacement formulation, Premarin. Previously, we have found that 4-OHEN rapidly autoxidized to an o-quinone in vitro and caused toxic effects such as the inactivation of human detoxification enzymes. 4-OHEN has also been shown to be a substrate for catechol-O-methyltransferase (COMT) in human breast cancer cells. In the present study, we demonstrated that 4-OHEN was not only a substrate of recombinant human soluble COMT in vitro with a K-m of 2.4 muM and k(cat) of 6.0 min(-1) but it also inhibited its own methylation by COMT at higher concentrations in the presence of the reducing agent dithiothreitol. In addition, 4-OHEN was found to be an irreversible inhibitor of COMT-catalyzed methylation of the endogenous catechol estrogen 4-hydroxyestradiol with a K-i of 26.0 muM and a k(2) of 1.62 x 10(-2) s(-1). 4-OHEN in vitro not only caused the formation of intermolecular disulfide bonds as demonstrated by gel electrophoresis, but electrospray ionization mass spectrometry and matrix-assisted laser desorption ionization time-of-flight mass spectrometry also showed that 4-OHEN alkylated multiple residues of COMT. Peptide mapping experiments further indicated that Cys33 in recombinant human soluble COMT was the residue most likely modified by 4-OHEN in vitro. These data suggest that inhibition of COMT methylation by 4-OHEN might reduce endogenous catechol estrogen clearance in vivo and further enhance toxicity. | - |
dc.format.extent | 8 | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | American Chemical Society | - |
dc.title | Catechol Estrogen 4-Hydroxyequilenin Is a Substrate and an Inhibitor of Catechol-O-Methyltransferase | - |
dc.type | Article | - |
dc.publisher.location | 미국 | - |
dc.identifier.doi | 10.1021/tx0340549 | - |
dc.identifier.scopusid | 2-s2.0-12444305981 | - |
dc.identifier.wosid | 000183058700013 | - |
dc.identifier.bibliographicCitation | Chemical Research in Toxicology, v.16, no.5, pp 668 - 675 | - |
dc.citation.title | Chemical Research in Toxicology | - |
dc.citation.volume | 16 | - |
dc.citation.number | 5 | - |
dc.citation.startPage | 668 | - |
dc.citation.endPage | 675 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalResearchArea | Chemistry | - |
dc.relation.journalResearchArea | Toxicology | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Medicinal | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Multidisciplinary | - |
dc.relation.journalWebOfScienceCategory | Toxicology | - |
dc.subject.keywordPlus | BREAST-CANCER RISKS | - |
dc.subject.keywordPlus | TRANSFERASE P1-1 | - |
dc.subject.keywordPlus | EQUINE ESTROGENS | - |
dc.subject.keywordPlus | DNA-DAMAGE | - |
dc.subject.keywordPlus | MOLECULAR MECHANISMS | - |
dc.subject.keywordPlus | CRYSTAL-STRUCTURE | - |
dc.subject.keywordPlus | HUMAN LIVER | - |
dc.subject.keywordPlus | METABOLITE | - |
dc.subject.keywordPlus | METHYLATION | - |
dc.subject.keywordPlus | QUINONES | - |
dc.identifier.url | https://pubs.acs.org/doi/10.1021/tx0340549 | - |
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