title: Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.
abstract: We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.
authors.affiliation: INSERM UMR 1037, Team Sterol Metabolism and Therapeutic Innovations in Oncology, Cancer Research Center of Toulouse, F-31052 Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: de Medina
authors.forename: Michael R
authors.initials: MR
authors.lastname: Paillasse
authors.forename: Gregory
authors.initials: G
authors.lastname: Segala
authors.forename: Maud
authors.initials: M
authors.lastname: Voisin
authors.forename: Loubna
authors.initials: L
authors.lastname: Mhamdi
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.forename: Frederic
authors.initials: F
authors.lastname: Pont
authors.forename: Talal Al
authors.initials: TA
authors.lastname: Saati
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001826:Body Fluids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007121:Immunocompetence / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D014020:Tissue Extracts
chemical_list: C582666:5-hydroxy-6-(2-(1H-imidazol-4-yl)ethylamino)cholestan-3-ol; D000970:Antineoplastic Agents; D002777:Cholestanols; D007093:Imidazoles; D011960:Receptors, Estrogen; D014020:Tissue Extracts; D006632:Histamine; D002784:Cholesterol; D004851:Epoxide Hydrolases; C019885:cholesterol-5 alpha,6 alpha-epoxide hydrase