CYP24A1 explained

Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D₃).^[1] It has also been identified as vitamin D3 24-hydroxylase.

Function

CYP24A1 is an enzyme expressed in the mitochondrion of humans and other species. It catalyzes hydroxylation reactions which lead to the degradation of 1,25-dihydroxyvitamin D₃, the physiologically active form of vitamin D. Hydroxylation of the side chain produces calcitroic acid and other metabolites which are excreted in bile.^{[1] [2]}

CYP24A1 was identified in the early 1970s and was first thought to be involved in vitamin D metabolism as the renal 25-hydroxyvitamin D3-24-hydroxylase, modifying calcifediol (25-hydroxyvitamin D) to produce 24,25-dihydroxycholecalciferol (24,25-dihydroxyvitamin D). Subsequent studies using recombinant CYP24A1 showed that it could also catalyze multiple other hydroxylation reactions at the side chain carbons known as C-24 and C-23 in both 25-OH-D₃ and the active hormonal form, 1,25-(OH)₂D₃. It is now considered responsible for the entire five-step, 24-oxidation pathway from 1,25-(OH)₂D₃ producing calcitroic acid.^[2]

CYP24A1 also is able to catalyze another pathway which starts with 23-hydroxylation of 1,25-(OH)₂D₃ and culminates in 1,25-(OH)₂D₃-26,23-lactone.^[2]

The side chains of the ergocalciferol (vitamin D₂) derivatives, 25-OH-D₂ and 1,25-(OH)₂D₂, are also hydroxylated by CYP24A1.^[2]

The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ.^[2] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

This enzyme plays an important role in calcium homeostasis and the vitamin D endocrine system through its regulation of the level of vitamin D₃.

Interactive pathway map

Regulation

CYP24A1 is expressed in tissues which are considered targets for vitamin D, including kidney, intestine and bone. Transcription of the CYP24A1 gene is markedly inducible by 1,25-(OH)₂D₃ binding to the vitamin D receptor.^[2] The gene has a strong, positive vitamin D response element in the promoter. Through regulation of CYP24A1 expression, a negative feedback control system is created to limit the effects of 1,25-(OH)₂D₃.^[2]

PTH and FGF23 also regulate CYP24A1 gene expression.^[2] Additionally, it is translationally regulated via IRES within the 5'UTR, which is responsive to an inflammatory environment.^[3]

Clinical relevance

Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia.^[4] However, increasingly patients are also being diagnosed in adulthood, often when they present with hypercalcaemia.^[5] Patients with mutations of the CYP24A1 gene have elevated serum calcium concentrations, elevated serum 1,25-(OH)₂D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and sometimes reduced bone density. Variations in the gene may also be found in people with renal stones.^[6]

Further reading

• Okuda K, Usui E, Ohyama Y . Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism . Journal of Lipid Research . 36 . 8 . 1641–52 . August 1995 . 10.1016/S0022-2275(20)41484-1 . 7595086 . free .
• Chen KS, DeLuca HF . Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1263 . 1 . 1–9 . July 1995 . 7632726 . 10.1016/0167-4781(95)00060-t .
• Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC . Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening . Genomics . 23 . 1 . 42–50 . September 1994 . 7829101 . 10.1006/geno.1994.1457 .
• Chen ML, Heinrich G, Ohyama YI, Okuda K, Omdahl JL, Chen TC, Holick MF . 22566441 . Expression of 25-hydroxyvitamin D3-24-hydroxylase mRNA in cultured human keratinocytes . Proceedings of the Society for Experimental Biology and Medicine . 207 . 1 . 57–61 . October 1994 . 7938037 . 10.3181/00379727-207-43791.
• Labuda M, Lemieux N, Tihy F, Prinster C, Glorieux FH . Human 25-hydroxyvitamin D 24-hydroxylase cytochrome P450 subunit maps to a different chromosomal location than that of pseudovitamin D-deficient rickets . Journal of Bone and Mineral Research . 8 . 11 . 1397–406 . November 1993 . 8266831 . 10.1002/jbmr.5650081114 . 32582996 .
• Hahn CN, Baker E, Laslo P, May BK, Omdahl JL, Sutherland GR . Grant Robert Sutherland . Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2→q13.3 . Cytogenetics and Cell Genetics . 62 . 4 . 192–3 . 1993 . 8440135 . 10.1159/000133473 .
• Chen KS, Prahl JM, DeLuca HF . Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA . Proceedings of the National Academy of Sciences of the United States of America . 90 . 10 . 4543–7 . May 1993 . 8506296 . 46548 . 10.1073/pnas.90.10.4543 . 1993PNAS...90.4543C . free .
• Bland R, Walker EA, Hughes SV, Stewart PM, Hewison M . Constitutive expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in a transformed human proximal tubule cell line: evidence for direct regulation of vitamin D metabolism by calcium . Endocrinology . 140 . 5 . 2027–34 . May 1999 . 10218951 . 10.1210/endo.140.5.6683 . free .
• Taniguchi T, Eto TA, Shiotsuki H, Sueta H, Higashi S, Iwamura T, Okuda KI, Setoguchi T . Newly established assay method for 25-hydroxyvitamin D3 24-hydroxylase revealed much lower Km for 25-hydroxyvitamin D3 than for 1alpha,25-dihydroxyvitamin D3 . Journal of Bone and Mineral Research . 16 . 1 . 57–62 . January 2001 . 11149490 . 10.1359/jbmr.2001.16.1.57 . 23117091 . free .
• Farhan H, Cross HS . Transcriptional inhibition of CYP24 by genistein . Annals of the New York Academy of Sciences . 973 . 1. 459–62 . November 2002 . 12485911 . 10.1111/j.1749-6632.2002.tb04683.x . 2002NYASA.973..459F . 30861453 .
• Theodoropoulos C, Demers C, Delvin E, Ménard D, Gascon-Barré M . Calcitriol regulates the expression of the genes encoding the three key vitamin D3 hydroxylases and the drug-metabolizing enzyme CYP3A4 in the human fetal intestine . Clinical Endocrinology . 58 . 4 . 489–99 . April 2003 . 12641633 . 10.1046/j.1365-2265.2003.01743.x . 44330630 .
• Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M . Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells . Blood . 102 . 9 . 3314–6 . November 2003 . 12855575 . 10.1182/blood-2002-11-3521 . free .
• Nguyen TM, Lieberherr M, Fritsch J, Guillozo H, Alvarez ML, Fitouri Z, Jehan F, Garabédian M . The rapid effects of 1,25-dihydroxyvitamin D3 require the vitamin D receptor and influence 24-hydroxylase activity: studies in human skin fibroblasts bearing vitamin D receptor mutations . The Journal of Biological Chemistry . 279 . 9 . 7591–7 . February 2004 . 14665637 . 10.1074/jbc.M309517200 . free .
• Mimori K, Tanaka Y, Yoshinaga K, Masuda T, Yamashita K, Okamoto M, Inoue H, Mori M . Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer . Annals of Oncology . 15 . 2 . 236–41 . February 2004 . 14760115 . 10.1093/annonc/mdh056 . free .
• Sawada N, Kusudo T, Sakaki T, Hatakeyama S, Hanada M, Abe D, Kamao M, Okano T, Ohta M, Inouye K . Novel metabolism of 1 alpha,25-dihydroxyvitamin D3 with C24-C25 bond cleavage catalyzed by human CYP24A1 . Biochemistry . 43 . 15 . 4530–7 . April 2004 . 15078099 . 10.1021/bi030207f .
• Kusudo T, Sakaki T, Abe D, Fujishima T, Kittaka A, Takayama H, Hatakeyama S, Ohta M, Inouye K . Metabolism of A-ring diastereomers of 1alpha,25-dihydroxyvitamin D3 by CYP24A1 . Biochemical and Biophysical Research Communications . 321 . 4 . 774–82 . September 2004 . 15358094 . 10.1016/j.bbrc.2004.07.040 .
• Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, Pineau T, Saric J, Navarro F, Maurel P, Vilarem MJ . Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia . The Journal of Clinical Investigation . 115 . 1 . 177–86 . January 2005 . 15630458 . 539191 . 10.1172/JCI21867 .

Notes and References

1. Web site: Entrez Gene: CYP24A1 cytochrome P450, family 24, subfamily A, polypeptide 1.
2. Jones G, Prosser DE, Kaufmann M . Cytochrome P450-mediated metabolism of vitamin D . Journal of Lipid Research . 55 . 1 . 13–31 . January 2014 . 23564710 . 10.1194/jlr.R031534 . free . 3927478.
3. Rübsamen D, Kunze MM, Buderus V, Brauß TF, Bajer MM, Brüne B, Schmid T . Inflammatory conditions induce IRES-dependent translation of cyp24a1 . PLOS ONE . 9 . 1 . e85314 . 1 January 2014 . 24416388 . 3885688 . 10.1371/journal.pone.0085314 . 2014PLoSO...985314R . free .
4. Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN . Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia . The Journal of Clinical Endocrinology and Metabolism . 97 . 2 . E268-74 . February 2012 . 22112808 . 3275367 . 10.1210/jc.2011-1972 .
5. Book: https://www.intechopen.com/books/a-critical-evaluation-of-vitamin-d-basic-overview/clinical-and-biochemical-features-of-patients-with-cyp24a1-mutations. 10.5772/64503. Clinical and Biochemical Features of Patients with CYP24A1 Mutations. A Critical Evaluation of Vitamin D - Basic Overview. 2017. 978-953-51-3083-3. 54572220 . Hill FJ, Sayer JA . IntechOpen .
6. Tebben PJ, Singh RJ, Kumar R . Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment . Endocrine Reviews . 37 . 5 . 521–547 . October 2016 . 27588937 . 10.1210/er.2016-1070 . 5045493.