| Sulfation of 4-hydroxy toremifene: individual variability, isoform specificity, and contribution to toremifene pharmacogenomics. | |
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MedLine Citation:
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PMID: 22434874 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Toremifene (TOR) is a selective estrogen receptor modulator used in adjuvant therapy for breast cancer and in clinical trials for prostate cancer prevention. The chemical structure of TOR differs from that of tamoxifen (TAM) by the presence of a chlorine atom in the ethyl side chain, resulting in a more favorable toxicity spectrum with TOR. In addition, some patients who fail on TAM therapy benefit from high-dose TOR therapy. Several studies have indicated that functional genetic variants in the TAM metabolic pathway influence response to therapy, but pharmacogenomic studies of patients treated with TOR are lacking. In this study, we examined individual variability in sulfation of 4-hydroxy TOR (4-OH TOR) (the active metabolite of TOR) in human liver cytosols from 104 subjects and found approximately 30-fold variation in activity. 4-OH TOR sulfation was significantly correlated (r = 0.98, P < 0.0001) with β-naphthol sulfation (diagnostic for SULT1A1) but not with 17β estradiol sulfation, a diagnostic substrate for SULT1E1(r = 0.09, P = 0.34). Examination of recombinant sulfotransferases (SULTs) revealed that SULT1A1 and SULT1E1 catalyzed 4-OH TOR sulfation, with apparent Km values of 2.6 and 6.4 μM and Vmax values of 8.5 and 5.5 nmol x min(-1) x mg protein(-1), respectively. 4-OH TOR sulfation was inhibited by 2,6-dichloro-4-nitrophenol (IC50 = 2.34 ± 0.19 μM), a specific inhibitor of SULT1A1. There was also a significant association between SULT1A1 genotypes and copy number and 4-OH TOR sulfation in human liver cytosols. These results indicate that variability in sulfation could contribute to response to TOR in the treatment of breast and prostate cancer. |
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Authors:
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Vineetha Koroth Edavana; Ishwori B Dhakal; Xinfeng Yu; Suzanne Williams; Susan Kadlubar |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-03-20 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 40 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-05-17 Completed Date: 2013-03-08 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 1210-5 Citation Subset: IM |
Affiliation:
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Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham, #580, Little Rock, AR 72205, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Aged Aged, 80 and over Arylsulfotransferase / genetics*, metabolism* Child Female Genetic Variation / physiology* Humans Liver / metabolism Male Middle Aged Pharmacogenetics* / methods Protein Isoforms / genetics, metabolism Selective Estrogen Receptor Modulators / metabolism Tamoxifen / analogs & derivatives*, metabolism Toremifene / metabolism* Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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R01-CA118981/CA/NCI NIH HHS; R01-CA128897/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Protein Isoforms; 0/Selective Estrogen Receptor Modulators; 10540-29-1/Tamoxifen; 110503-62-3/4-hydroxytoremifene; 89778-26-7/Toremifene; EC 2.8.2.1/Arylsulfotransferase; EC 2.8.2.1/SULT1A1 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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