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Metabolism of a nov...
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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 ...
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Elsevier BV,2008
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-100754
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100754URI
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https://doi.org/10.1016/j.bbalip.2008.05.009DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:117557568URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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)
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Andersson, UllaAvd. för klinisk kemi, KI, Huddinge, Sverige
(author)
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Pikuleva, IrinaDepartment of clinical chemistry and toxicology, University of Texas medical branch, Galveston, USA
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Björkhem, IngemarKarolinska Institutet
(author)
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Misharin, Alexander YuInst. of biomedical chemisrty, Russian academy of medical sciences, Moscow, Russia
(author)
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Wikvall, KjellUppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450(Swepub:uu)kwi24506
(author)
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Uppsala universitetAvdelningen för farmaceutisk biokemi
(creator_code:org_t)
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