title: 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.
authors.affiliation: INSERM UMR 1037-Cancer Research Center of Toulouse, Université de Toulouse III, Institut Claudius Regaud, Toulouse,  France.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Paillasse
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saffon
authors.forename: Heinz
authors.initials: H
authors.lastname: Gornitzka
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.forename: Philippe
authors.initials: P
authors.lastname: de Medina
mesh_terms: D000478:Alkylation; D002384:Catalysis; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003470:Culture Media / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D019856:Ethanolamine / Q000737:chemistry; D006147:Guanine / Q000737:chemistry; D008623:Mercaptoethanol / Q000737:chemistry; D008958:Models, Molecular; D013237:Stereoisomerism
chemical_list: C119784:5,6-epoxycholesterol; D003470:Culture Media; D004852:Epoxy Compounds; C002415:cholesterol alpha-oxide; D019856:Ethanolamine; D006147:Guanine; D008623:Mercaptoethanol; D002784:Cholesterol; C013690:styrene oxide