Lumisterol is metabolized by CYP11A1: Discovery of a new pathway

Abstract

Lumisterol3 (L3) is produced by photochemical transformation of 7-dehydrocholesterol (7-DHC) during exposure to high doses of ultraviolet B radiation. It has been assumed that L3 is biologically inactive and is not metabolized in the body. However, some synthetic derivatives of L3 display biological activity. The aim of this study was to test the ability of CYP11A1 to metabolize L3. Incubation of L3 with bovine or human CYP11A1 resulted in the formation of three major and a number of minor products. The catalytic efficiency of bovine CYP11A1 for metabolism of L3 dissolved in 2-hydroxypropyl-β-cyclodextrin was approximately 20% of that reported for vitamin D3 and cholesterol. The structures of the three major products were identified as 24-hydroxy-L3, 22-hydroxy-L3 and 20,22-dihydroxy-L3 by NMR. 22-hydroxy-L3 was further metabolized by bovine CYP11A1 to 20,22-dihydroxy-L3. Both 22-hydroxy-L3 and 20,22-dihydroxy-L3 gave rise to a minor metabolite identified from authentic standard and mass spectrometry as pregnalumisterol (pL) (product of C20-C22 side chain cleavage of L3) and two trihydroxy-L3 products. The capability of tissues expressing CYP11A1 to metabolize L3 was demonstrated using pig adrenal fragments where 20,22-dihydroxy-L3, 22-hydroxy-L3, 24-hydroxy-L3 and pL were detected by LC/MS. Thus, we have established that L3 is metabolized by CYP11A1 to 22- and 24-hydroxy-L3 and 20,22-dihydroxy-L3 as major products, as well as to pL and other minor products. The previously reported biological activity of pL and the presence of CYP11A1 in skin suggest that this pathway may serve to produce biologically active products from L3, emphasizing a novel role of CYP11A1 in sterol metabolism.

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…This involved hydroxylations at C22 and C20 followed by oxidative cleavage of the bond between C20 and C22 to produce pregnenolone, a precursor to all steroids [41, 42]. However, the expression of CYP11A1 in peripheral tissues, albeit at low levels, has now been documented [43] and alternative substrates to cholesterol have been identified experimentally, such as 7DHC, vitamins D2 and D3, ergosterol and lumisterol [44–49]. Additionally, the possibility of other sterol/secosteroidal compounds serving as substrates has been predicted theoretically based on molecular modeling [50].…”

The role of tachysterol in vitamin D photosynthesis – a non-adiabatic molecular dynamics study

“…As second dominant reaction channel, we observe in 10 trajectories (2.3 %) [1,5]-sigmatropic hydrogen transfer from carbon C-19 to carbon C-7, forming the experimentally confirmed 83,84 partly deconjugated 9,10-seco-triene toxisterol D1 (Toxi-D1) ( Fig. 8b and Fig.…”

“…3, right). In one trajectory we find a reversible [1,5]-hydrogen shift from C-19 to C-7 before the double bond isomerizes ( Fig. 12 and 13).…”

“…3, right). This is expected, since [1,5]-sigmatropic hydrogen transfer requires carbons C-19 and C-7 to be close enough to react, which is only fulfilled by cEc and cEt conformers. Relating the hydrogen-transfer trajectories with the initial excitation energy (Fig.…”

“…Besides regulating calcium uptake and controlling bone growth, Vita is involved in the regulation of apoptosis, 1 autoimmune diseases, 2 cardiovascular diseases, 3 and plays a role in the natural prevention and treatment of cancer. 4,5 Tachysterol (Tachy) is often considered a side product in vitamin D photosynthesis, but several studies indicate its importance in the regulation of vitamin D photo production. 6,7 Similar to other vitamin D photo isomers (DPI), also Tachy and its metabolites possess biologic activity.…”