A novel pathway for sequential transformation of 7‐dehydrocholesterol and expression of the P450scc system in mammalian skin

Following up on our previous findings that the skin possesses steroidogenic activity from progesterone, we now show widespread cutaneous expression of the full cytochrome P450 side‐chain cleavage (P450scc) system required for the intracellular catalytic production of pregnenolone, i.e. the genes and...

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Bibliographic Details
Published in:European journal of biochemistry 2004-11, Vol.271 (21), p.4178-4188
Main Authors: Slominski, Andrzej, Zjawiony, Jordan, Wortsman, Jacobo, Semak, Igor, Stewart, Jeremy, Pisarchik, Alexander, Sweatman, Trevor, Marcos, Josep, Dunbar, Chuck, C. Tuckey, Robert
Format: Article
Language:English
Subjects:
7‐dehydrocholesterol
7‐dehydropregnenolone
Adrenodoxin - metabolism
Animals
Blotting, Western
Catalysis
Cattle
Cell Line
Chromatography, High Pressure Liquid
Chromatography, Liquid
Chromatography, Thin Layer
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - metabolism
cytochrome P450scc
Dehydrocholesterols - chemistry
DNA Primers - chemistry
Ferredoxin-NADP Reductase - metabolism
Fibroblasts - metabolism
Gas Chromatography-Mass Spectrometry
Humans
Kinetics
Magnetic Resonance Spectroscopy
Male
Mass Spectrometry
Mice
Mice, Inbred C57BL
Mitochondria - metabolism
Models, Chemical
Placenta - metabolism
Pregnenolone - analogs & derivatives
Pregnenolone - chemistry
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
skin
Skin - metabolism
Time Factors
ultraviolet radiation
Ultraviolet Rays
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Summary:Following up on our previous findings that the skin possesses steroidogenic activity from progesterone, we now show widespread cutaneous expression of the full cytochrome P450 side‐chain cleavage (P450scc) system required for the intracellular catalytic production of pregnenolone, i.e. the genes and proteins for P450scc enzyme, adrenodoxin, adrenodoxin reductase and MLN64. Functionality of the system was confirmed in mitochondria from skin cells. Moreover, purified mammalian P450scc enzyme and, most importantly, mitochondria isolated from placenta and adrenals produced robust transformation of 7‐dehydrocholesterol (7‐DHC; precursor to cholesterol and vitamin D3) to 7‐dehydropregnenolone (7‐DHP). Product identity was confirmed by comparison with the chemically synthesized standard and chromatographic, MS and NMR analyses. Reaction kinetics for the conversion of 7‐DHC into 7‐DHP were similar to those for cholesterol conversion into pregnenolone. Thus, 7‐DHC can form 7‐DHP through P450scc side‐chain cleavage, which may serve as a substrate for further conversions into hydroxy derivatives through existing steroidogenic enzymes. In the skin, 5,7‐steroidal dienes (7‐DHP and its hydroxy derivatives), whether synthesized locally or delivered by the circulation, may undergo UVB‐induced intramolecular rearrangements to vitamin D3‐like derivatives. This novel pathway has the potential to generate a variety of molecules depending on local steroidogenic activity and access to UVB.
ISSN:0014-2956
1742-464X
1432-1033
1742-4658
DOI:10.1111/j.1432-1033.2004.04356.x