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

Pettersson, Hanna (author): Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450

Norlin, Maria (author): Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450

Andersson, Ulla (author): Avd. för klinisk kemi, KI, Huddinge, Sverige

Pikuleva, Irina (author): Department of clinical chemistry and toxicology, University of Texas medical branch, Galveston, USA

Björkhem, Ingemar (author): Karolinska Institutet

Misharin, Alexander Yu (author): Inst. of biomedical chemisrty, Russian academy of medical sciences, Moscow, Russia

Wikvall, Kjell (author): Uppsala universitet,Avdelningen för farmaceutisk biokemi,Steroid P450

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Elsevier BV, 2008
2008
English.
In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981 .- 1879-2618. ; 1781:8, s. 383-390

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Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Keyword

human CYP27A1
27-hydroxylation
28-hydroxylation
inhibitors of sterol biosynthesis
cholesterol lowering drug
Pharmaceutical biochemistry
Farmaceutisk biokemi
Biokemi
Biochemistry

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art (subject category)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

Articles in the publication: Biochimica et Bi ...; Biochimica et bi ...

By the university: Uppsala University; Karolinska Institutet

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