3.3.1. DDA is enzymatically produced in normal tissues
Researchers have hypothesized that 5,6-EC could be metabolized into
inducers of cell-differentiation such as dendrogenin A for several
reasons: 1) ChEH contains the microsomal anti-oestrogen binding site
(AEBS) which controls BC cell death and differentiation, showing that
5,6-EC and 5,6-EC metabolites mediated BC cell differentiation(de Medina
et al., 2009; Payre et al., 2008; Segala et al., 2013; Silvente-Poirot
& Poirot, 2012); 2) ChEH subunits EBP and DHCR7 are required for human
development programs (Herman, 2003; Porter & Herman, 2011) opening up
the possibilities that ChEH activity and 5,6-EC metabolites could
contribute to development programs as inducers of cell differentiation;
3) at the chemical level, 5,6α-EC was found to be reactive towards
nucleophilic groups such as mercaptant and amines only in the presence
of a catalyst and give a single conjugated stereoisomer amongst multiple
possibilities(Silvente-Poirot, de Medina, Record & Poirot, 2016). This
supported the possible existence of a new metabolic branch based on
5,6α-EC stereospecific conjugation since homochirality is a common
occurence in life (Blackmond, 2019; Fujii & Saito, 2004); 4) the AEBS
binds 5,6-EC and nucleophilic substances such as histamine or polyamines
opening up a possibility of conjugation reaction at the ChEH level
(Leignadier, Dalenc, Poirot & Silvente-Poirot, 2017). The chemical
synthesis of 5,6α-EC conjugation products with certain biogenic amines
including histamine and polyamine has been performed(de Medina,
Paillasse, Payre, Silvente-Poirot & Poirot, 2009). As expected, 5,6α-EC
conjugates displayed strong cell differentiation properties in
vitro (de Medina, Paillasse, Payre, Silvente-Poirot & Poirot, 2009).
Amongst these conjugates, the histaminic adduct called dendrogenin A
(DDA), was found to induce cell differentiation properties in
pluripotent undifferentiated cells (de Medina, Paillasse, Payre,
Silvente-Poirot & Poirot, 2009) and normal progenitor cells (Khalifa,
de Medina, Erlandsson, El-Seedi, Silvente-Poirot & Poirot, 2014). DDA
was reported to induce cell differentiation and death in mouse and human
cells of various tissue origins (Bauriaud-Mallet et al., 2019; de
Medina, Paillasse, Payre, Silvente-Poirot & Poirot, 2009; de Medina et
al., 2013). More specifically DDA was found to induce BC cell
re-differentiation to produce breast epithelial-like cells
(Bauriaud-Mallet et al., 2019; de Medina, Paillasse, Payre,
Silvente-Poirot & Poirot, 2009; de Medina et al., 2013). The production
of chemical tools such as radio- and deuterium-labelled DDA, and the
development of analytical methods has made possible the detection and
quantification of DDA in mammalian tissues which has led to the
demonstration that DDA exists in mammals (de Medina et al., 2013; Soules
et al., 2019). DDA can be formed in mammalian tissue from 5,6α-EC and
histamine and this reaction was shown to require a proteinaceous enzyme
that remains to be identified (de Medina et al., 2013). Cultured normal
breast epithelial cells produced DDA, while DDA was not detectable in BC
cell lines (de Medina et al., 2013). This suggests that a deregulation
in DDA metabolism could occur during oncogenesis and it may result from
an alteration of the DDA metabolism in epithelial cells. This was
confirmed in patients by comparing DDA levels in BC tumours and normal
adjacent tissues (de Medina et al., 2013). Interestingly, thanks to the
improvement of analytical methods for DDA quantification, dendrogenin B
which is a 5,6α-EC conjugate of spermidine with neurodifferentiation and
neurone regeneration properties (Dalenc, Poirot & Silvente-Poirot,
2015; de Medina, Paillasse, Payre, Silvente-Poirot & Poirot, 2009;
Fransson, de Medina, Paillasse, Silvente-Poirot, Poirot & Ulfendahl,
2015; Khalifa, de Medina, Erlandsson, El-Seedi, Silvente-Poirot &
Poirot, 2014) was found to exist as a mammalian metabolite (Soules et
al., 2019). This showed that a new metabolic branch existed in the
cholesterol pathway and this branch is centered around 5,6α-EC
conjugation and produces inducers of cell differentiation.