Lumisterol is metabolized by CYP11A1: Discovery of a new pathway

Robert Tuckey, A.T. Słomiński, Chloe Cheng, J. Chen, T. Kim, M. Xiao, W. Li

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. © 2014 Elsevier Ltd.
Original languageEnglish
Pages (from-to)24-34
JournalInternational Journal of Biochemistry and Cell Biology
Volume55
DOIs
Publication statusPublished - 2014

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Cholesterol Side-Chain Cleavage Enzyme
Ergosterol
Bioactivity
Metabolism
Cholecalciferol
Cyclodextrins
Sterols
Metabolites
Dosimetry
Mass spectrometry
Mass Spectrometry
Skin
Swine
Cholesterol
Nuclear magnetic resonance
Radiation
Tissue
Derivatives

Cite this

Tuckey, Robert ; Słomiński, A.T. ; Cheng, Chloe ; Chen, J. ; Kim, T. ; Xiao, M. ; Li, W. / Lumisterol is metabolized by CYP11A1: Discovery of a new pathway. In: International Journal of Biochemistry and Cell Biology. 2014 ; Vol. 55. pp. 24-34.
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title = "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. {\circledC} 2014 Elsevier Ltd.",
author = "Robert Tuckey and A.T. Słomiński and Chloe Cheng and J. Chen and T. Kim and M. Xiao and W. Li",
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Lumisterol is metabolized by CYP11A1: Discovery of a new pathway. / Tuckey, Robert; Słomiński, A.T.; Cheng, Chloe; Chen, J.; Kim, T.; Xiao, M.; Li, W.

In: International Journal of Biochemistry and Cell Biology, Vol. 55, 2014, p. 24-34.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lumisterol is metabolized by CYP11A1: Discovery of a new pathway

AU - Tuckey, Robert

AU - Słomiński, A.T.

AU - Cheng, Chloe

AU - Chen, J.

AU - Kim, T.

AU - Xiao, M.

AU - Li, W.

PY - 2014

Y1 - 2014

N2 - 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. © 2014 Elsevier Ltd.

AB - 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. © 2014 Elsevier Ltd.

U2 - 10.1016/j.biocel.2014.08.004

DO - 10.1016/j.biocel.2014.08.004

M3 - Article

VL - 55

SP - 24

EP - 34

JO - The International Journal of Biochemistry & Cell Biology

JF - The International Journal of Biochemistry & Cell Biology

SN - 1357-2725

ER -