Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles. - Archive ouverte HAL Access content directly
Journal Articles Journal of Lipid Research Year : 2012

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

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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.

Dates and versions

inserm-00743457 , version 1 (19-10-2012)

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Michael R. 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, 2012, 53 (4), pp.718-25. ⟨10.1194/jlr.M023689⟩. ⟨inserm-00743457⟩
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