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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Body Fluids / metabolism
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Brain / metabolism
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cholestanols / chemistry
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Cholestanols / pharmacology*
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Cholestanols / therapeutic use
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Cholesterol / metabolism*
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Epoxide Hydrolases / antagonists & inhibitors
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Epoxide Hydrolases / metabolism
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Female
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Histamine / metabolism*
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Humans
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Immunocompetence / drug effects
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Lymphocytes / drug effects
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Receptors, Estrogen / metabolism
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Survival Analysis
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Tissue Extracts
Substances
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5-hydroxy-6-(2-(1H-imidazol-4-yl)ethylamino)cholestan-3-ol
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Antineoplastic Agents
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Cholestanols
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Imidazoles
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Receptors, Estrogen
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Tissue Extracts
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Histamine
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Cholesterol
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Epoxide Hydrolases
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cholesterol-5 alpha,6 alpha-epoxide hydrase