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Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1
Fulvestrant (Faslodex™) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fu...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400326/ https://www.ncbi.nlm.nih.gov/pubmed/22822301 http://dx.doi.org/10.2147/PGPM.S25418 |
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author | Edavana, Vineetha Koroth Yu, Xinfeng Dhakal, Ishwori B Williams, Suzanne Ning, Baitang Cook, Ian T Caldwell, David Falany, Charles N Kadlubar, Susan |
author_facet | Edavana, Vineetha Koroth Yu, Xinfeng Dhakal, Ishwori B Williams, Suzanne Ning, Baitang Cook, Ian T Caldwell, David Falany, Charles N Kadlubar, Susan |
author_sort | Edavana, Vineetha Koroth |
collection | PubMed |
description | Fulvestrant (Faslodex™) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with K(m) of 4.2 ± 0.99 and 0.2 ± 0.16 μM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with β-naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001), but not with 17β-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10). Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023) and copy number (P < 0.0001). These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy. |
format | Online Article Text |
id | pubmed-3400326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-34003262012-07-19 Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 Edavana, Vineetha Koroth Yu, Xinfeng Dhakal, Ishwori B Williams, Suzanne Ning, Baitang Cook, Ian T Caldwell, David Falany, Charles N Kadlubar, Susan Pharmgenomics Pers Med Original Research Fulvestrant (Faslodex™) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with K(m) of 4.2 ± 0.99 and 0.2 ± 0.16 μM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with β-naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001), but not with 17β-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10). Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023) and copy number (P < 0.0001). These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy. Dove Medical Press 2011-11-17 /pmc/articles/PMC3400326/ /pubmed/22822301 http://dx.doi.org/10.2147/PGPM.S25418 Text en © 2011 Edavana et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. |
spellingShingle | Original Research Edavana, Vineetha Koroth Yu, Xinfeng Dhakal, Ishwori B Williams, Suzanne Ning, Baitang Cook, Ian T Caldwell, David Falany, Charles N Kadlubar, Susan Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title | Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title_full | Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title_fullStr | Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title_full_unstemmed | Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title_short | Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1 |
title_sort | sulfation of fulvestrant by human liver cytosols and recombinant sult1a1 and sult1e1 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400326/ https://www.ncbi.nlm.nih.gov/pubmed/22822301 http://dx.doi.org/10.2147/PGPM.S25418 |
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