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). It has also been identified as vitamin D3 24-hydroxylase.(EC 126.96.36.199)
|, CP24, CYP24, HCAI, P450-CC24, cytochrome P450 family 24 subfamily A member 1, HCINF1|
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.
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.
CYP24A1 also is able to catalyse another pathway which starts with 23-hydroxylation of 1,25-(OH)2D3 and culminates in 1,25-(OH)2D3-26,23-lactone.
The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ. 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 mapEdit
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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. 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.
Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia. 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.
- GRCh38: Ensembl release 89: ENSG00000019186 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000038567 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Entrez Gene: CYP24A1 cytochrome P450, family 24, subfamily A, polypeptide 1".
- Jones G, Prosser DE, Kaufmann M (January 2014). "Cytochrome P450-mediated metabolism of vitamin D". Journal of Lipid Research. 55 (1): 13–31. doi:10.1194/jlr.R031534. PMC 3927478. PMID 23564710.
- Rübsamen D, Kunze MM, Buderus V, Brauß TF, Bajer MM, Brüne B, Schmid T (2014-01-01). "Inflammatory conditions induce IRES-dependent translation of cyp24a1". PLOS ONE. 9 (1): e85314. doi:10.1371/journal.pone.0085314. PMC 3885688. PMID 24416388.
- Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN (February 2012). "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. doi:10.1210/jc.2011-1972. PMC 3275367. PMID 22112808.
- Tebben PJ, Singh RJ, Kumar R (October 2016). "Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment". Endocrine Reviews. 37 (5): 521–547. doi:10.1210/er.2016-1070. PMC 5045493. PMID 27588937.
- Okuda K, Usui E, Ohyama Y (August 1995). "Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism". Journal of Lipid Research. 36 (8): 1641–52. PMID 7595086.
- Chen KS, DeLuca HF (July 1995). "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. 1263 (1): 1–9. doi:10.1016/0167-4781(95)00060-t. PMID 7632726.
- Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC (September 1994). "Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening". Genomics. 23 (1): 42–50. doi:10.1006/geno.1994.1457. PMID 7829101.
- Chen ML, Heinrich G, Ohyama YI, Okuda K, Omdahl JL, Chen TC, Holick MF (October 1994). "Expression of 25-hydroxyvitamin D3-24-hydroxylase mRNA in cultured human keratinocytes". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 207 (1): 57–61. doi:10.3181/00379727-207-43791. PMID 7938037.
- Labuda M, Lemieux N, Tihy F, Prinster C, Glorieux FH (November 1993). "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. doi:10.1002/jbmr.5650081114. PMID 8266831.
- Hahn CN, Baker E, Laslo P, May BK, Omdahl JL, Sutherland GR (1993). "Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2-->q13.3". Cytogenetics and Cell Genetics. 62 (4): 192–3. doi:10.1159/000133473. PMID 8440135.
- Chen KS, Prahl JM, DeLuca HF (May 1993). "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. doi:10.1073/pnas.90.10.4543. PMC 46548. PMID 8506296.
- Bland R, Walker EA, Hughes SV, Stewart PM, Hewison M (May 1999). "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. doi:10.1210/en.140.5.2027. PMID 10218951.
- Taniguchi T, Eto TA, Shiotsuki H, Sueta H, Higashi S, Iwamura T, Okuda KI, Setoguchi T (January 2001). "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. doi:10.1359/jbmr.2001.16.1.57. PMID 11149490.
- Farhan H, Cross HS (November 2002). "Transcriptional inhibition of CYP24 by genistein". Annals of the New York Academy of Sciences. 973: 459–62. doi:10.1111/j.1749-6632.2002.tb04683.x. PMID 12485911.
- Theodoropoulos C, Demers C, Delvin E, Ménard D, Gascon-Barré M (April 2003). "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. doi:10.1046/j.1365-2265.2003.01743.x. PMID 12641633.
- Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M (November 2003). "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. doi:10.1182/blood-2002-11-3521. PMID 12855575.
- Nguyen TM, Lieberherr M, Fritsch J, Guillozo H, Alvarez ML, Fitouri Z, Jehan F, Garabédian M (February 2004). "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. doi:10.1074/jbc.M309517200. PMID 14665637.
- Mimori K, Tanaka Y, Yoshinaga K, Masuda T, Yamashita K, Okamoto M, Inoue H, Mori M (February 2004). "Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer". Annals of Oncology. 15 (2): 236–41. doi:10.1093/annonc/mdh056. PMID 14760115.
- Sawada N, Kusudo T, Sakaki T, Hatakeyama S, Hanada M, Abe D, Kamao M, Okano T, Ohta M, Inouye K (April 2004). "Novel metabolism of 1 alpha,25-dihydroxyvitamin D3 with C24-C25 bond cleavage catalyzed by human CYP24A1". Biochemistry. 43 (15): 4530–7. doi:10.1021/bi030207f. PMID 15078099.
- Kusudo T, Sakaki T, Abe D, Fujishima T, Kittaka A, Takayama H, Hatakeyama S, Ohta M, Inouye K (September 2004). "Metabolism of A-ring diastereomers of 1alpha,25-dihydroxyvitamin D3 by CYP24A1". Biochemical and Biophysical Research Communications. 321 (4): 774–82. doi:10.1016/j.bbrc.2004.07.040. PMID 15358094.
- Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, Pineau T, Saric J, Navarro F, Maurel P, Vilarem MJ (January 2005). "Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia". The Journal of Clinical Investigation. 115 (1): 177–86. doi:10.1172/JCI21867. PMC 539191. PMID 15630458.