Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1

Vineetha Koroth Edavana, Xinfeng Yu, Ishwori B. Dhakal, Suzanne Williams, Baitang Ning, Ian T. Cook, David Caldwell, Charles N. Falany, Susan Kadlubar

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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 Km 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.

Original languageEnglish (US)
Pages (from-to)137-145
Number of pages9
JournalPharmacogenomics and Personalized Medicine
Volume4
Issue number1
StatePublished - Dec 22 2011
Externally publishedYes

Keywords

  • Copy number
  • Fulvestrant
  • Genotype
  • Sulfotransferase

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Edavana, V. K., Yu, X., Dhakal, I. B., Williams, S., Ning, B., Cook, I. T., Caldwell, D., Falany, C. N., & Kadlubar, S. (2011). Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1. Pharmacogenomics and Personalized Medicine, 4(1), 137-145.