Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies.

Abstract

Free radical chain oxidation of highly oxidizable 7-dehydrocholesterol (7-DHC), initiated by 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), was carried out at 37 degrees C in benzene for 24 h. Fifteen oxysterols derived from 7-DHC were isolated and characterized with 1D and 2D NMR spectroscopy and mass spectrometry. A mechanism that involves abstraction of hydrogen atoms at C-9 and/or C-14 is proposed to account for the formation of all of the oxysterols and the reaction progress profile. In either the H-9 or H-14 mechanism, a pentadienyl radical intermediate is formed after abstraction of H-9 or H-14 by a peroxyl radical. This step is followed by the well-precedented transformations observed in peroxidation reactions of polyunsaturated fatty acids such as oxygen addition, peroxyl radical 5-exo cyclization, and S(H)i carbon radical attack on the peroxide bond. The mechanism for peroxidation of 7-DHC also accounts for the formation of numerous oxysterol natural products isolated from fungal species, marine sponges, and cactaceous species. In a cell viability test, the oxysterol mixture from 7-DHC peroxidation was found to be cytotoxic to Neuro2a neuroblastoma cells in the micromolar concentration range. We propose that the high reactivity of 7-DHC and the oxysterols generated from its peroxidation may play important roles in the pathogenesis of Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata, and cerebrotendinous xanthomatosis, all of these being metabolic disorders characterized by an elevated level of 7-DHC.

• Authors: Libin Xu, Zeljka Korade, Ned A Porter
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 132 Issue 7 Pg. 2222-32 (Feb 24 2010) ISSN: 1520-5126 [Electronic] United States
• PMID: 20121089 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Azo Compounds
• Dehydrocholesterols
• Free Radicals
• Nitriles
• Sterols
• V 70
• 7-dehydrocholesterol

Topics

• Animals
• Azo Compounds (chemistry)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dehydrocholesterols (chemistry, metabolism)
• Free Radicals (chemistry, metabolism)
• Mice
• Neuroblastoma (drug therapy, pathology)
• Nitriles (chemistry)
• Nuclear Magnetic Resonance, Biomolecular
• Oxidation-Reduction
• Rats
• Sterols (chemistry, metabolism, pharmacology)