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

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 journal › Article › peer-review

20 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 language	English (US)
Pages (from-to)	137-145
Number of pages	9
Journal	Pharmacogenomics and Personalized Medicine
Volume	4
Issue number	1
State	Published - Dec 22 2011
Externally published	Yes

Keywords

Copy number
Fulvestrant
Genotype
Sulfotransferase

ASJC Scopus subject areas

Molecular Medicine
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

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title = "Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1",

abstract = "Fulvestrant (Faslodex{\texttrademark}) 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.",

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T1 - Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1

AU - Edavana, Vineetha Koroth

AU - Yu, Xinfeng

AU - Dhakal, Ishwori B.

AU - Williams, Suzanne

AU - Ning, Baitang

AU - Cook, Ian T.

AU - Caldwell, David

AU - Falany, Charles N.

AU - Kadlubar, Susan

PY - 2011/12/22

Y1 - 2011/12/22

N2 - 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.

AB - 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.

KW - Copy number

KW - Fulvestrant

KW - Genotype

KW - Sulfotransferase

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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