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Metabolism of a nov...
Metabolism of a novel side chain modified Delta 8(14)-15-ketosterol, a potential cholesterol lowering drug : 28-hydroxylation by CYP27A1
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- Pettersson, Hanna (författare)
- Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450
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- Norlin, Maria (författare)
- Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450
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- Andersson, Ulla (författare)
- Avd. för klinisk kemi, KI, Huddinge, Sverige
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- Pikuleva, Irina (författare)
- Department of clinical chemistry and toxicology, University of Texas medical branch, Galveston, USA
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- Björkhem, Ingemar (författare)
- Karolinska Institutet
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- Misharin, Alexander Yu (författare)
- Inst. of biomedical chemisrty, Russian academy of medical sciences, Moscow, Russia
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- Wikvall, Kjell (författare)
- Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450
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(creator_code:org_t)
- Elsevier BV, 2008
- 2008
- Engelska.
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1781:8, s. 383-390
- Relaterad länk:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- The synthetic inhibitors of sterol biosynthesis, 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one and 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3beta-Hydroxy-5alpha-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side chain modified 15-ketosterol 3beta-Hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7alpha-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one than with the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. A surprising finding was that this novel side chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- human CYP27A1
- 27-hydroxylation
- 28-hydroxylation
- inhibitors of sterol biosynthesis
- cholesterol lowering drug
- Pharmaceutical biochemistry
- Farmaceutisk biokemi
- Biokemi
- Biochemistry
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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