2. The 5,6-epoxycholesterols (5,6-ECs)
5,6-ECs exist as two different diastereoisomers: the 5,6α-EC and the
5,6β-EC (Fig 1A). They stem from the mono-oxygenation of cholesterol on
its Δ5,6-double bond. In biological systems they can
be produced as a mixture via a free radical lipid peroxidation process
(Iuliano, 2011; Poirot & Silvente-Poirot, 2013; Porter, Xu & Pratt,
2020; Yin, Xu & Porter, 2011). The stereo-selective synthesis of
5,6β-EC can be achieve using porphyrins, that mimic cytochrome p450
monooxygenases(Poirot & Silvente-Poirot, 2013), and a stereoselective
biosynthesis of 5,6α-EC by a yet unidentified cytochrome p450 have been
described in bovine adrenals (Watabe & Sawahata, 1979). 5,6-EC are
known as major autoxidation and photo-oxidation products of cholesterol
(Smith, 1981). They are present in biological fluids and solid tissues
from mammals (Poirot & Silvente-Poirot, 2013; Schroepfer, 2000).
The epoxide ring, is well known by chemists for its reactivity towards
nucleophilic groups and is widely used for this reason in organic
chemistry (Gorzynski Smith, 1984; Parker & Isaacs, 1959). 5,6α -EC was
suspected to be involved in skin photocarcinogenesis as it accumulated
in skin after UV exposure (Black & Douglas, 1973; Black & Lo, 1971; Lo
& Black, 1973; Lo & Black, 1972) and activated a ChEH activity to
accelerate the hydrolysis and elimination of 5,6-EC (Chan & Black,
1974). Meanwhile, 5,6-EC were found to be chemically stable towards
nucleophiles ruling out a direct carcinogenic activity (Paillasse,
Saffon, Gornitzka, Silvente-Poirot, Poirot & de Medina, 2012).
In the presence of a catalyst 5,6α-EC was the only of the two 5,6-ECs
that reacts with nucleophiles to give a single product of addition with
a 5α-6β stereochemistry through a trans-diaxial ring opening (Paillasse,
Saffon, Gornitzka, Silvente-Poirot, Poirot & de Medina, 2012; Poirot &
Silvente-Poirot, 2013) (Fig 1B). 5,6-EC were reported to be modulators
of nuclear receptors such as Liver-X-Receptors α (LXRα) and β (LXRβ)
(Berrodin, Shen, Quinet, Yudt, Freedman & Nagpal, 2010; Song, Hiipakka
& Liao, 2001) showing that these oxysterols are biologically active
oxysterols. The metabolism of 5,6-EC has been previously reviewed and
showed that 5,6α-EC and 5,6β-EC were differentially metabolized in
mammals (Poirot & Silvente-Poirot, 2013). Interestingly, 5,6β-EC was
reported to accumulate in breast nipple fluids from patients with BC and
preneoplastic breast lesions supporting that the 5,6-EC metabolism was
linked to breast carcinogenesis (Gruenke, Wrensch, Petrakis, Miike,
Ernster & Craig, 1987; Petrakis, Gruenke & Craig, 1981; Wrensch et
al., 1989).