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|Title:||High-affinity binding sites for oxygenated sterols in rat liver microsomes: Possible identity with antiestrogen binding sites||Authors:||Hwang, P.L.H.||Keywords:||antiestrogen
antiestrogen binding site
oxysterol binding protein
|Issue Date:||1990||Citation:||Hwang, P.L.H. (1990). High-affinity binding sites for oxygenated sterols in rat liver microsomes: Possible identity with antiestrogen binding sites. Biochimica et Biophysica Acta - General Subjects 1033 (2) : 154-161. ScholarBank@NUS Repository. https://doi.org/10.1016/0304-4165(90)90006-I||Abstract:||Oxygenated derivatives of cholesterol are known to exhibit a number of biological activities including the inhibition of cholesterol biosynthesis and of cell proliferation, but their mechanism of action remains unclear. Previous studies have identified a cytosolic protein which binds 25-hydroxycholesterol, as well as several other oxysterols, with high affinity, possibly mediating some of their effects. We now report the existence of a high-affinity oxysterol binding site in rat liver microsomes which is distinct from the cytosolic binding protein. Among the oxygenated sterols examined, 5α-cholestan-3β-ol-7-one (7-ketocholestanol) had the highest affinity for this microsomal binding site (K(d) = 2.7 nM). Using 7-keto[3H]cholestanol as the radioactive ligand, we found that binding of this oxysterol to the microsomal binding site was saturable and reversible and was displaceable by the following oxysterols in descending order of potency: 7-ketocholestanol > 6-ketocholestanol > 7β-hydroxycholesterol = 7-ketocholesterol > cholesten-3β,5α,6β-triol = 7α-hydroxycholesterol > 4-cholesten-3-one. All other sterols studied, including, notably, 25-hydroxycholesterol, had little or no inhibitory effect on 7-keto[3H]cholestanol binding. Additional studies revealed that the microsomal oxysterol binding site was probably identical to the antiestrogen binding site described by other workers. First, saturation analysis and kinetic studies demonstrated that the antiestrogen tamoxifen competed directly with 7-keto[3H]cholestanol for the same binding site. Second, the ability of different oxysterols and antiestrogens to inhibit 7-keto[3H]cholestanol binding to the microsomal binding site paralleled their ability to inhibit [3H]tamoxifen binding to the antiestrogen binding site. Third, the tissue distribution of binding sites for 7-keto[3H]cholestanol was similar to that of the antiestrogen binding site. We conclude that: (1) in rat liver microsomes there are high-affinity oxysterol binding sites whose ligand specificity is different from that of the cytosolic oxysterol binding protein; and (2) the microsomal oxysterol binding site is probably identical to the antiestrogen binding site. The biological significance of these observations remains to be explored.||Source Title:||Biochimica et Biophysica Acta - General Subjects||URI:||http://scholarbank.nus.edu.sg/handle/10635/107471||ISSN:||03044165||DOI:||10.1016/0304-4165(90)90006-I|
|Appears in Collections:||Staff Publications|
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