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

被引：100

作者：

de Medina, Philippe ^{[1
,2
]}

Paillasse, Michael R. ^{[1
,2
]}

Segala, Gregory ^{[1
,3
,4
]}

Voisin, Maud ^{[1
,3
,4
]}

Mhamdi, Loubna ^{[2
]}

Dalenc, Florence ^{[1
,3
,4
]}

Lacroix-Triki, Magali ^{[3
,4
]}

Filleron, Thomas ^{[4
]}

Pont, Frederic ^{[5
]}

Al Saati, Talal ^{[6
]}

Morisseau, Christophe ^{[7
,8
]}

Hammock, Bruce D. ^{[7
,8
]}

Silvente-Poirot, Sandrine ^{[1
,3
,4
]}

Poirot, Marc ^{[1
,3
,4
]}

机构：

[1] Canc Res Ctr Toulouse, INSERM, UMR 1037, Team Sterol Metab & Therapeut Innovat Oncol, F-31052 Toulouse, France

[2] AFFICHEM, F-31052 Toulouse, France

[3] Univ Toulouse 3, F-31052 Toulouse, France

[4] Inst Claudius Regaud, F-31052 Toulouse, France

[5] Univ Toulouse 3, CNRS, UDEAR, UMR 5165, F-31059 Toulouse, France

[6] CREFRE, INSERM, ANEXPLO US006, F-31024 Toulouse, France

[7] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA

[8] Univ Calif Davis, UCD Comprehens Canc Ctr, Davis, CA 95616 USA

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

关键词：

MICROSOMAL EPOXIDE HYDROLASE; ESTROGEN-RECEPTOR MODULATORS; BINDING-SITE LIGANDS; BREAST-CANCER CELLS; AEBS LIGANDS; RAT-LIVER; SQUALAMINE; TAMOXIFEN; OXYSTEROLS; GROWTH;

D O I：

10.1038/ncomms2835

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 5,6 alpha-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.

引用

页数：10

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