The serum vitamin D metabolome: What we know and what is still to discover

Robert C. Tuckey, Chloe Y. S. Cheng, Andrzej T. Slominski

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)(2)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1 alpha,25(OH)(2)D. Inactivation of both 25(OH)D and la,25(OH)(2)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)(2)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1 alpha,25(OH)(2)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)(2)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.

Original languageEnglish
Pages (from-to)4-21
Number of pages18
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume186
DOIs
Publication statusPublished - Feb 2019

Cite this

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title = "The serum vitamin D metabolome: What we know and what is still to discover",
abstract = "Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)(2)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1 alpha,25(OH)(2)D. Inactivation of both 25(OH)D and la,25(OH)(2)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)(2)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1 alpha,25(OH)(2)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)(2)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.",
keywords = "Vitamin D, 25-Hydroxyvitamin D3, Metabolome, LC/MS/MS, Cytochrome P450, 25-HYDROXYVITAMIN D-3 1-ALPHA-HYDROXYLASE, CHROMATOGRAPHY-MASS SPECTROMETRY, BIOLOGICAL-ACTIVITY ASSESSMENT, A-RING DIASTEREOMERS, LC-MS/MS METHOD, 1-ALPHA,25-DIHYDROXYVITAMIN D-3, LIQUID-CHROMATOGRAPHY, CYTOCHROME P450SCC, D-RECEPTOR, 20-HYDROXYVITAMIN D3",
author = "Tuckey, {Robert C.} and Cheng, {Chloe Y. S.} and Slominski, {Andrzej T.}",
year = "2019",
month = "2",
doi = "10.1016/j.jsbmb.2018.09.003",
language = "English",
volume = "186",
pages = "4--21",
journal = "Journal of Steroid Biochemistry & Molecular Biology",
issn = "0960-0760",
publisher = "Pergamon",

}

The serum vitamin D metabolome : What we know and what is still to discover. / Tuckey, Robert C.; Cheng, Chloe Y. S.; Slominski, Andrzej T.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 186, 02.2019, p. 4-21.

Research output: Contribution to journalReview article

TY - JOUR

T1 - The serum vitamin D metabolome

T2 - What we know and what is still to discover

AU - Tuckey, Robert C.

AU - Cheng, Chloe Y. S.

AU - Slominski, Andrzej T.

PY - 2019/2

Y1 - 2019/2

N2 - Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)(2)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1 alpha,25(OH)(2)D. Inactivation of both 25(OH)D and la,25(OH)(2)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)(2)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1 alpha,25(OH)(2)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)(2)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.

AB - Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)(2)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1 alpha,25(OH)(2)D. Inactivation of both 25(OH)D and la,25(OH)(2)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)(2)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1 alpha,25(OH)(2)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)(2)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.

KW - Vitamin D

KW - 25-Hydroxyvitamin D3

KW - Metabolome

KW - LC/MS/MS

KW - Cytochrome P450

KW - 25-HYDROXYVITAMIN D-3 1-ALPHA-HYDROXYLASE

KW - CHROMATOGRAPHY-MASS SPECTROMETRY

KW - BIOLOGICAL-ACTIVITY ASSESSMENT

KW - A-RING DIASTEREOMERS

KW - LC-MS/MS METHOD

KW - 1-ALPHA,25-DIHYDROXYVITAMIN D-3

KW - LIQUID-CHROMATOGRAPHY

KW - CYTOCHROME P450SCC

KW - D-RECEPTOR

KW - 20-HYDROXYVITAMIN D3

U2 - 10.1016/j.jsbmb.2018.09.003

DO - 10.1016/j.jsbmb.2018.09.003

M3 - Review article

VL - 186

SP - 4

EP - 21

JO - Journal of Steroid Biochemistry & Molecular Biology

JF - Journal of Steroid Biochemistry & Molecular Biology

SN - 0960-0760

ER -