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

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 5,6 alpha-epoxy-cholesterol (5,6 alpha-EC) and 5,6 beta-epoxy-cholesterol (5,6 beta-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, 5,6 beta-EC remains unreactive whereas 5,6 alpha-EC gives cholestan-3 beta,5 alpha-diol-6 beta-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.(jlr) These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6 alpha-EC.-Paillasse, M. R., N. Saffon, H. Gornitzka, S. Silvente-Poirot, M. Poirot, and P. de Medina. Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles. J. Lipid Res. 2012. 53: 718-725.