Document Detail


Metabolism of a novel side chain modified Delta8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1.
MedLine Citation:
PMID:  18603016     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hanna Pettersson; Maria Norlin; Ulla Andersson; Irina Pikuleva; Ingemar Björkhem; Alexander Yu Misharin; Kjell Wikvall
Related Documents :
24774576 - Pharmacogenetic study of the response to flecainide and propafenone in patients with at...
19877686 - Solar uv-b radiation influences carotenoid accumulation of tomato fruit through both et...
23629886 - Balancing the energy budget in free-ranging male myotis daubentonii bats.
24810916 - Circadian rhythms, insulin action, and glucose homeostasis.
16647536 - Gerbilline cholesteatoma development part i: epithelial migration pattern and rate on t...
3972676 - Submandibular and disseminated zygomycosis (mucormycosis) in feeder pigs.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-06-11
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1781     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-11     Completed Date:  2008-10-03     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  383-90     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Anticholesteremic Agents / metabolism*
Cell Line
Cholestanetriol 26-Monooxygenase / metabolism*
Cholestenones / chemistry,  metabolism*
Chromatography, High Pressure Liquid
Ethers / metabolism
Humans
Hydroxylation
Kinetics
Mass Spectrometry
Microsomes, Liver / metabolism
Recombinant Proteins / metabolism
Grant Support
ID/Acronym/Agency:
EY018383/EY/NEI NIH HHS; R01 EY018383/EY/NEI NIH HHS; R01 EY018383-01/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/3-hydroxy-24-methylcholesta-8(14),22-dien-15-one; 0/Anticholesteremic Agents; 0/Cholestenones; 0/Ethers; 0/Recombinant Proteins; EC 1.14.13.15/Cholestanetriol 26-Monooxygenase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Polymorphisms in metabolic GSTP1 and DNA-repair XRCC1 genes with an increased risk of DNA damage in ...
Next Document:  The alchemy of immune privilege explored from a neuroimmunological perspective.