In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1

Andrzej T. Slominski, Tae Kang Kim, Haleem Z. Shehabi, Igor Semak, Edith K.Y. Tang, Minh N. Nguyen, Heather A.E. Benson, Elena Korik, Zorica Janjetovic, Jianjun Chen, Charles Yates, Arnold Postlethwaite, Wei Li, Robert C. Tuckey

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3-hydroxyderivatives different from 25-hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20-hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ∼20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α-hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH) 2D3 → 17,20,23(OH)3D3 with further 1α-hydroxylation, and minor pathways were D3 → 25(OH)D3 →1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH) 2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH) 2D3.

Original languageEnglish (US)
Pages (from-to)3901-3915
Number of pages15
JournalFASEB Journal
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2012

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25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Cholecalciferol
Metabolism
Cholesterol Side-Chain Cleavage Enzyme
Keratinocytes
Adrenal Glands
Placenta
Calcifediol
Hydroxylation
Organ Specificity
Mitochondria
Enzymes
Metabolites
Mixed Function Oxygenases
20-hydroxyvitamin D3
Biological Products
Vitamin D
20,23-dihydroxyvitamin D3

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Slominski, A. T., Kim, T. K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., ... Tuckey, R. C. (2012). In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. FASEB Journal, 26(9), 3901-3915. https://doi.org/10.1096/fj.12-208975

In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. / Slominski, Andrzej T.; Kim, Tae Kang; Shehabi, Haleem Z.; Semak, Igor; Tang, Edith K.Y.; Nguyen, Minh N.; Benson, Heather A.E.; Korik, Elena; Janjetovic, Zorica; Chen, Jianjun; Yates, Charles; Postlethwaite, Arnold; Li, Wei; Tuckey, Robert C.

In: FASEB Journal, Vol. 26, No. 9, 01.09.2012, p. 3901-3915.

Research output: Contribution to journalArticle

Slominski, AT, Kim, TK, Shehabi, HZ, Semak, I, Tang, EKY, Nguyen, MN, Benson, HAE, Korik, E, Janjetovic, Z, Chen, J, Yates, C, Postlethwaite, A, Li, W & Tuckey, RC 2012, 'In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1', FASEB Journal, vol. 26, no. 9, pp. 3901-3915. https://doi.org/10.1096/fj.12-208975
Slominski, Andrzej T. ; Kim, Tae Kang ; Shehabi, Haleem Z. ; Semak, Igor ; Tang, Edith K.Y. ; Nguyen, Minh N. ; Benson, Heather A.E. ; Korik, Elena ; Janjetovic, Zorica ; Chen, Jianjun ; Yates, Charles ; Postlethwaite, Arnold ; Li, Wei ; Tuckey, Robert C. / In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. In: FASEB Journal. 2012 ; Vol. 26, No. 9. pp. 3901-3915.
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AU - Kim, Tae Kang

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AU - Semak, Igor

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AU - Nguyen, Minh N.

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