title: Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties.
abstract: Cholesterol-5,6-epoxide hydrolase (ChEH) in mammals is a heterooligomeric complex of two cholesterogenic enzymes that control mammalian developmental programs. Following the identification of this complex, it was hypothesized that a new metabolic pathway existed that centered on 5,6-epoxy cholesterols (5,6-EC). Conjugation products of 5,6-EC with biogenic amines known to interact with ChEH subunits were synthesized. According to their structures, these steroidal alkaloids showed the specific potency to induce cell differentiation at low doses, suggesting their possible existence as metabolites. One of these compounds, named dendrogenin A (DDA), was recently discovered in mammalian tissues. It was shown that DDA arises from the stereoselective enzymatic conjugation of 5,6α-epoxy-cholesterol with histamine by an as-yet-unidentified enzyme. DDA was detected in normal tissues from several organs but not in cancer cells and its level was decreased in breast tumors from patients, evidencing a deregulation of DDA metabolism during carcinogenesis. DDA was also able to control the growth of tumor cells implanted in mice and improve animal survival. In addition, DDA efficiently restored hearing in a preclinical model of deafness. These biological properties of DDA, as well as its decreased levels in tumors, suggest a physiological function in maintaining cell integrity and differentiation. DDA is the first steroidal alkaloid found to date in mammals. Its discovery reveals the existence of a new metabolic pathway in mammals at the crossroads of cholesterol and histamine metabolism that leads to the production of a metabolic tumor suppressor and neuroprotective agent.
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.affiliation: Department of Sterol Metabolism, Cancer Research Center of Toulouse, INSERM UMR 1037-University of Toulouse, P.O. Box: 31017, Toulouse, France. marc.poirot@inserm.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002777:Cholestanols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy
chemical_list: C582666:5-hydroxy-6-(2-(1H-imidazol-4-yl)ethylamino)cholestan-3-ol; D000970:Antineoplastic Agents; D002777:Cholestanols; D007093:Imidazoles; D002784:Cholesterol