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Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles.

Abstract : We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6β-epoxy-cholesterol (5,6β-EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6β-EC remains unreactive whereas 5,6α-EC gives cholestan-3β,5α-diol-6β-substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6α-EC.
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https://www.hal.inserm.fr/inserm-00743457
Contributor : Marc Poirot <>
Submitted on : Friday, October 19, 2012 - 9:25:23 AM
Last modification on : Tuesday, June 30, 2020 - 3:10:55 AM

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Michael Paillasse, Nathalie Saffon, Heinz Gornitzka, Sandrine Silvente-Poirot, Marc Poirot, et al.. Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles.. Journal of Lipid Research, American Society for Biochemistry and Molecular Biology, 2012, 53 (4), pp.718-25. ⟨10.1194/jlr.M023689⟩. ⟨inserm-00743457⟩

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