Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties

• Published in: Nature communications Vol. 4; no. 1; p. 1840
• Main Authors: de Medina, Philippe, Paillasse, Michael R., Segala, Gregory, Voisin, Maud, Mhamdi, Loubna, Dalenc, Florence, Lacroix-Triki, Magali, Filleron, Thomas, Pont, Frederic, Saati, Talal Al, Morisseau, Christophe, Hammock, Bruce D., Silvente-Poirot, Sandrine, Poirot, Marc
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/67; 631/92/1643; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding sites; Biosynthesis; Body Fluids - metabolism; Brain - metabolism; Breast cancer; Cell Differentiation - drug effects; Cell Line, Tumor; Cholestanols - chemistry; Cholestanols - pharmacology; Cholestanols - therapeutic use; Cholesterol; Cholesterol - metabolism; Chromatography; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Female; Histamine; Histamine - metabolism; Humanities and Social Sciences; Humans; Hypotheses; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; Immunocompetence - drug effects; Life Sciences; Ligands; Lymphocytes - drug effects; Lymphocytes - metabolism; Lymphocytes - pathology; Metabolism; Metabolites; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmaceutical sciences; Receptors, Estrogen - metabolism; Science; Science (multidisciplinary); Survival Analysis; Tissue Extracts; Tumors; France; anti-tumor; cell differentiation; histamine; 6-epoxide hydrolase; survival; epoxy-cholesterol; cholesterol; melanoma; Breast cancer; mice; cholesterol-5
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2835

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. It has been hypothesized that the steroidal alkaloid dendrogenin A (DDA) is a natural metabolite. de Medina et al. show that DDA is produced in mammalian tissues from 5,6α-epoxy-cholesterol and histamine metabolism, and that the compound displays cell differentiation and anti-tumour activities.