CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells

Elizabeth T Jacobs, Chad Van Pelt, Ryan E. Forster, Wasiq Zaidi, Elizabeth A. Hibler, Michael A. Galligan, Mark R Haussler, Peter W. Jurutka

Research output: Contribution to journalArticle

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Abstract

Vitamin D is a well-studied agent for cancer chemoprevention and treatment. Its chief circulating metabolite, 25-hydroxyvitamin D, is converted into the active hormone 1,25-dihydroxyvitamin D (1,25D) by the cytochrome P450 enzyme CYP27B1 in kidney and other tissues. 1,25D is then deactivated by CYP24A1 and ultimately catabolized. Colorectal carcinoma cells express CYP27B1 and CYP24A1 that locally regulate 1,25D with potential implications for its impact on carcinogenesis. While 1,25D inhibits cancer growth, the effects of polymorphic variations in genes encoding proteins involved in 1,25D homeostasis are poorly understood. Using an RXR-VDR mammalian two-hybrid (M2H) biologic assay system, we measured vitaminDmetabolite uptake and activation of the vitamin D receptor (VDR) pathway in colon cancer cells that expressed one of five CYP27B1 single-nucleotide polymorphisms (SNP) or four CYP24A1 SNPs. Compared with the wild-type control, four of five CYP27B1 SNPs reduced enzymatic activity, whereas one (V166L) increased activity. For CYP24A1, all tested SNPs reduced enzyme activity. Quantitative real-time PCR analyses supported the results of M2H experiments. The observed SNP-directed variation in CYP functionality indicated that vitamin D homeostasis is complex and may be influenced by genetic factors. A comprehensive understanding of 1,25D metabolism may allow for a more personalized approach toward treating vitamin D-related disorders and evaluating risk for carcinogenesis.

Original languageEnglish (US)
Pages (from-to)2563-2573
Number of pages11
JournalCancer Research
Volume73
Issue number8
DOIs
StatePublished - Apr 15 2013

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25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Vitamin D
Colonic Neoplasms
Single Nucleotide Polymorphism
Calcitriol Receptors
Cytochrome P-450 Enzyme System
Carcinogenesis
Homeostasis
Chemoprevention
Biological Assay
1,25-dihydroxyvitamin D
Vitamin D3 24-Hydroxylase
Real-Time Polymerase Chain Reaction
Colorectal Neoplasms
Neoplasms
Hormones
Kidney
Enzymes
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jacobs, E. T., Van Pelt, C., Forster, R. E., Zaidi, W., Hibler, E. A., Galligan, M. A., ... Jurutka, P. W. (2013). CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells. Cancer Research, 73(8), 2563-2573. https://doi.org/10.1158/0008-5472.CAN-12-4134

CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells. / Jacobs, Elizabeth T; Van Pelt, Chad; Forster, Ryan E.; Zaidi, Wasiq; Hibler, Elizabeth A.; Galligan, Michael A.; Haussler, Mark R; Jurutka, Peter W.

In: Cancer Research, Vol. 73, No. 8, 15.04.2013, p. 2563-2573.

Research output: Contribution to journalArticle

Jacobs, ET, Van Pelt, C, Forster, RE, Zaidi, W, Hibler, EA, Galligan, MA, Haussler, MR & Jurutka, PW 2013, 'CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells', Cancer Research, vol. 73, no. 8, pp. 2563-2573. https://doi.org/10.1158/0008-5472.CAN-12-4134
Jacobs, Elizabeth T ; Van Pelt, Chad ; Forster, Ryan E. ; Zaidi, Wasiq ; Hibler, Elizabeth A. ; Galligan, Michael A. ; Haussler, Mark R ; Jurutka, Peter W. / CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells. In: Cancer Research. 2013 ; Vol. 73, No. 8. pp. 2563-2573.
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