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  • Pettersson, HannaUppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450 (author)

Metabolism of a novel side chain modified Delta 8(14)-15-ketosterol, a potential cholesterol lowering drug : 28-hydroxylation by CYP27A1

  • Article/chapterEnglish2008

Publisher, publication year, extent ...

  • Elsevier BV,2008
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-100754
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100754URI
  • https://doi.org/10.1016/j.bbalip.2008.05.009DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:117557568URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Norlin, MariaUppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450(Swepub:uu)mno24506 (author)
  • Andersson, UllaAvd. för klinisk kemi, KI, Huddinge, Sverige (author)
  • Pikuleva, IrinaDepartment of clinical chemistry and toxicology, University of Texas medical branch, Galveston, USA (author)
  • Björkhem, IngemarKarolinska Institutet (author)
  • Misharin, Alexander YuInst. of biomedical chemisrty, Russian academy of medical sciences, Moscow, Russia (author)
  • Wikvall, KjellUppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450(Swepub:uu)kwi24506 (author)
  • Uppsala universitetAvdelningen för farmaceutisk biokemi (creator_code:org_t)

Related titles

  • In:Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids: Elsevier BV1781:8, s. 383-3901388-19811879-2618
  • In:Biochimica et biophysica acta: Elsevier BV1781:8, s. 383-3900006-3002

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