Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties

Title:Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties

Volume: 22 Issue: 30

Author(s): Florence Dalenc, Marc Poirot and Sandrine Silvente-Poirot

Affiliation:

Keywords: AEBS, cancer, cholesterol, cholesterol-5, 6-epoxide hydrolase, dendrogenin, steroidal alkaloid, tamoxifen.

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.

Cite this article as:

Dalenc Florence, Poirot Marc and Silvente-Poirot Sandrine, Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties, Current Medicinal Chemistry 2015; 22 (30) . https://dx.doi.org/10.2174/0929867322666150716114912