title: Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1.
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 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.
authors: Division of Medical genetics, college of Medicine, University of Arkansas for Medical sciences, Little rock, AR, USA.
authors: Vineetha Koroth
authors: VK
authors: Edavana
authors: Xinfeng
authors: X
authors: Yu
authors: Ishwori B
authors: IB
authors: Dhakal
authors: Suzanne
authors: S
authors: Williams
authors: Baitang
authors: B
authors: Ning
authors: Ian T
authors: IT
authors: Cook
authors: David
authors: D
authors: Caldwell
authors: Charles N
authors: CN
authors: Falany
authors: Susan
authors: S
authors: Kadlubar