The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2024 Jun 27

PMID 38927120

Authors

Minori Uga

Ichiro Kaneko

Yuji Shiozaki

Megumi Koike

Naoko Tsugawa

Peter W Jurutka

Ken-Ichi Miyamoto

Hiroko Segawa

Affiliations

Soon will be listed here.

Abstract

Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D [1,25(OH)D]. 1,25(OH)D controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH)D-VDRE activity. Moreover, in mice, mRNA was significantly induced by 1,25(OH)D in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH)D, and this mitochondrial enzyme appears to hydroxylate 25OHD to 24,25(OH)D. Thus, CYP3A or CYP24A1 could locally attenuate 25OHD or 1,25(OH)D action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue.

References

Ren S, Nguyen L, Wu S, Encinas C, Adams J, Hewison M . Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis. J Biol Chem. 2005; 280(21):20604-11. DOI: 10.1074/jbc.M414522200. View

Yasuda K, Nishikawa M, Okamoto K, Horibe K, Mano H, Yamaguchi M . Elucidation of metabolic pathways of 25-hydroxyvitamin D3 mediated by CYP24A1 and CYP3A using Cyp24a1 knockout rats generated by CRISPR/Cas9 system. J Biol Chem. 2021; 296:100668. PMC: 8134072. DOI: 10.1016/j.jbc.2021.100668. View

Fagerberg L, Hallstrom B, Oksvold P, Kampf C, Djureinovic D, Odeberg J . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2013; 13(2):397-406. PMC: 3916642. DOI: 10.1074/mcp.M113.035600. View

Choi K, Jeung E . Molecular mechanism of regulation of the calcium-binding protein calbindin-D9k, and its physiological role(s) in mammals: a review of current research. J Cell Mol Med. 2008; 12(2):409-20. PMC: 3822532. DOI: 10.1111/j.1582-4934.2007.00209.x. View

van Abel M, Hoenderop J, Bindels R . The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease. Naunyn Schmiedebergs Arch Pharmacol. 2005; 371(4):295-306. DOI: 10.1007/s00210-005-1021-2. View

Aspelund T, Grubler M, Smith A, Gudmundsson E, Keppel M, Cotch M . Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts. Nutrients. 2019; 11(1). PMC: 6356674. DOI: 10.3390/nu11010074. View

Meisenheimer P, Uyeda H, Ma D, Sobol M, McDougall M, Corona C . Proluciferin acetals as bioluminogenic substrates for cytochrome P450 activity and probes for CYP3A inhibition. Drug Metab Dispos. 2011; 39(12):2403-10. DOI: 10.1124/dmd.111.041541. View

Hawkes C, Li D, Hakonarson H, Meyers K, Thummel K, Levine M . CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab. 2017; 102(5):1440-1446. PMC: 5443336. DOI: 10.1210/jc.2016-4048. View

Lips P . Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001; 22(4):477-501. DOI: 10.1210/edrv.22.4.0437. View

10.

Watkins P, Wrighton S, Schuetz E, Molowa D, Guzelian P . Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest. 1987; 80(4):1029-36. PMC: 442342. DOI: 10.1172/JCI113156. View

11.

Lee S, Riley E, Meyer M, Benkusky N, Plum L, Deluca H . 1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target Genes in the Proximal Intestine That Is Enriched for Calcium-regulating Components. J Biol Chem. 2015; 290(29):18199-18215. PMC: 4505063. DOI: 10.1074/jbc.M115.665794. View

12.

Paschen S, Neupert W . Protein import into mitochondria. IUBMB Life. 2002; 52(3-5):101-12. DOI: 10.1080/15216540152845894. View

13.

Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P . Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest. 2012; 122(5):1803-15. PMC: 3336970. DOI: 10.1172/JCI45890. View

14.

Wang Z, Lin Y, Dickmann L, Poulton E, Eaton D, Lampe J . Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia. J Bone Miner Res. 2012; 28(5):1101-16. PMC: 3609874. DOI: 10.1002/jbmr.1839. View

15.

Lehmann J, McKee D, Watson M, Willson T, Moore J, Kliewer S . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998; 102(5):1016-23. PMC: 508967. DOI: 10.1172/JCI3703. View

16.

Zanger U, Schwab M . Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138(1):103-41. DOI: 10.1016/j.pharmthera.2012.12.007. View

17.

Burgos-Trinidad M, Ismail R, Ettinger R, Prahl J, DeLuca H . Immunopurified 25-hydroxyvitamin D 1 alpha-hydroxylase and 1,25-dihydroxyvitamin D 24-hydroxylase are closely related but distinct enzymes. J Biol Chem. 1992; 267(5):3498-505. View

18.

Wang Y, Zhu J, Deluca H . Where is the vitamin D receptor?. Arch Biochem Biophys. 2012; 523(1):123-33. DOI: 10.1016/j.abb.2012.04.001. View

19.

Guengerich F . Inhibition of Cytochrome P450 Enzymes by Drugs-Molecular Basis and Practical Applications. Biomol Ther (Seoul). 2021; 30(1):1-18. PMC: 8724836. DOI: 10.4062/biomolther.2021.102. View

20.

Moore L, Parks D, Jones S, Bledsoe R, Consler T, Stimmel J . Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem. 2000; 275(20):15122-7. DOI: 10.1074/jbc.M001215200. View