24-Hydroxycholesterol sulfation by human cytosolic sulfotransferases: Formation of monosulfates and disulfates, molecular modeling, sulfatase sensitivity, and inhibition of liver X receptor activation

Ian T. Cook, Zofia Duniec-Dmuchowski, Thomas A. Kocarek, Melissa Runge-Morris, Charles N. Falany

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24-Hydroxycholesterol (24-OHChol) is a major cholesterol metabolite and the form in which cholesterol is secreted from the brain. 24-OHChol is transported by apolipoprotein E to the liver and converted into bile acids or excreted. In both brain and liver, 24-OHChol is a liver X receptor (LXR) agonist and has an important role in cholesterol homeostasis. 24-OHChol sulfation was examined to understand its role in 24-OHChol metabolism and its effect on LXR activation. 24-OHChol was conjugated by three isoforms of human cytosolic sulfotransferase (SULT). SULT2A1 and SULT1E1 sulfated both the 3- and 24-hydroxyls to form the 24-OHChol-3, 24-disulfate. SULT2B1b formed only 24-OHChol-3-sulfate. The 3-sulfate as a monosulfate or as the disulfate was hydrolyzed by human placental steroid sulfatase, whereas the 24-sulfate was resistant. At physiological 24-OHChol concentrations, SULT2A1 formed the 3-monosulfate and the 3, 24-disulfate as a result of a high affinity for sulfation of the 3-OH in 24-OHChol-24-sulfate. Molecular docking simulations indicate that 24-OHChol-24-sulfate binds in an active configuration in the SULT2A1 substrate binding site with high affinity only when the SULT2A1 homodimer structure was used. 24-OHChol is an LXR activator. In contrast, the 24-OHChol monosulfates were not LXR agonists in a fluorescence resonance energy transfer coactivator recruitment assay. However, both the 24-OHChol-3-sulfate and 24-sulfate were antagonists of LXR activation by N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro- 1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) with an IC50 of 0.15 and 0.31 μM, respectively. Inhibition of LXR activation by the 24-OHChol monosulfates at low nanomolar concentrations indicates that sulfation has a role in LXR regulation by oxysterols.

Original languageEnglish (US)
Pages (from-to)2069-2078
Number of pages10
JournalDrug Metabolism and Disposition
Issue number10
Publication statusPublished - Oct 1 2009


ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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