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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The CYP27B1 gene maps to chromosome 12q14.1 and has nine exons spanning ~6.5 kb in length (Fu et al. 1997). The CYP27B1 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, zebrafish, and frog. The gene encodes a 508–amino acid protein. CYP27B1 (also called mitochondrial 25-hydroxyvitamin D 1α hydroxylase) localizes to the inner mitochondrial membrane where it hydroxylates 25(OH)D3 at the 1α-position to form active 1α,25(OH)2D3 (Zehnder et al. 1999). This is the rate-limiting step in the bioactivation of vitamin D. CYP27B1 is present in the distal convoluted tubule, the cortical and medullary part of the collecting duct, and the papillary epithelia of kidney, and lower expression is found in the loop of Henle and Bowman’s capsule, glomeruli, and vasculature structures (Zehnder et al. 1999). CYP27B1 is also expressed in skin, lymph nodes, colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex) (Zehnder et al. 2001), placenta (decidual and trophoblastic cells) (Diaz et al. 2002; Zehnder et al. 2001), cervix (Friedrich et al. 2002), and parathyroid glands (Segersten et al. 2002). 1α-Hydroxylase activity in extrarenal tissues is an important source of 1,25(OH)2D3 for
Other bone diseases in the elderly
Published in Charles M Court-Brown, Margaret M McQueen, Marc F Swiontkowski, David Ring, Susan M Friedman, Andrew D Duckworth, Musculoskeletal Trauma in the Elderly, 2016
Patients with chronic kidney disease (CKD) are at greatly increased risk of bone disease and this may take several forms, including osteoporosis, osteomalacia and secondary hyperparathyroidism. Osteoporosis is the most common problem and reflecting this fact, patients with CKD are at markedly increased risk of fracture as compared with the general population.46 The sequence of events underlying these abnormalities is complex as depicted in Figure 11.5. There is reduced production of 1,25(OH)2D due in part to an inhibitory effect of hyperphosphataemia on the CYP27B1 enzyme in the renal tubules. Production of the phosphaturic hormone FGF23 by osteocytes is increased in response to hyperphosphataemia and this also exerts an inhibitory effect on CYP27B1. Serum calcium levels fall as the result of the hyperphosphataemia which makes complexes with calcium causing soft tissue calcification and as the result of reduced intestinal calcium absorption because of the low 125(OH)2D levels. This stimulates PTH secretion from the parathyroid glands, which increases bone turnover causing bone loss and in some cases, osteitis fibrosa cystica and osteomalacia.
Nutrition and bone health during childhood and adolescence: A global perspective
Published in Nicholas C. Harvey, Cyrus Cooper, Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Kate A Ward, Ann Prentice, Shane A Norris, John M Pettifor
Rickets due to low dietary calcium intakes may occur in the face of 25(OH)D concentrations which are generally considered to be within the normal range (>30 nmol/L), however low dietary calcium intakes may also exacerbate the development of rickets in children who have a poor vitamin D status (57). As discussed above, the pathogenesis of rickets due to low dietary calcium intakes is very similar to that of vitamin D deficiency, except that serum 1,25-dihydroxyvitamin D concentrations are typically markedly elevated in untreated patients with dietary calcium deficiency, as a consequence of the upregulation of CYP27B1 (1-alpha hydroxylase) by elevated parathyroid hormone (PTH) levels. Rickets due to low dietary calcium intakes have been described in a number of LMIC, such as South Africa, Nigeria, The Gambia, India and Bangladesh, where dairy product consumption is negligible and phytate ingestion (which binds dietary calcium) is typically high. Calcium consumption by children with active rickets in these communities has been estimated to be around 200 mg/day. Characteristically, children suffering from rickets due to low dietary calcium intakes are older than those with vitamin D deficiency. In large studies from Nigeria, the age at presentation was approximately 4 years, while in South Africa the children ranged from 4 to 16 years of age. Although low dietary calcium intakes appear to be central to the pathogenesis of nutritional rickets in these communities, it is unclear what predisposes some children to develop rickets while others with similar dietary calcium intakes do not. Genetic factors, dietary constituents besides calcium and levels of 25(OH)D may all play a role.
Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Jiří Janoušek, Veronika Pilařová, Kateřina Macáková, Anderson Nomura, Jéssica Veiga-Matos, Diana Dias da Silva, Fernando Remião, Luciano Saso, Kateřina Malá-Ládová, Josef Malý, Lucie Nováková, Přemysl Mladěnka
Malfunctions of any mentioned enzyme can cause human disease [155]. With increasing age, the ability of kidneys to activate 25(OH)D3 declines. Also, increased expression of CYP24A1 and increased calcitriol clearance have been described [156–158]. These factors may contribute to age-related bone thinning. Inborn diseases can also affect vitamin D metabolism. Vitamin D-dependent rickets (VDDR) type 1 is caused by an inactivating mutation in the CYP27B1 gene, subsequently leading to insufficient 1α-hydroxylation and thus reduced activation of 25(OH)D3 [159]. There is also a rare hereditary variant of VDDR called type 1 b in which the loss-of-function mutation occurs in CYP2R1, leading to low levels of 25(OH)D [160]. VDDR type 3 is associated with the gain-of-function mutation in the substrate recognition site of CYP3A4, which thereafter starts to extensively deactivate calcitriol [161]. The mechanisms of vitamin D metabolism-mediated rickets as well as other genetically based rickets are schematically depicted in Figure 5 and summarized in Table 2.
Vitamin D Receptor (VDR) Allelic Variants Correlating with Response to Vitamin D3 Supplementation in Breast Cancer Survivors
Published in Nutrition and Cancer, 2022
Elham Kazemian, Sayed Hossein Davoodi, Mohammad Esmaeil Akbari, Nariman Moradi, Safoora Gharibzadeh, Alison M Mondul, Yasaman Jamshidi-Naeini, Maryam Khademolmele, Katie R. Zarins, Nasim Ghodoosi, Laura S. Rozek, Atieh Amouzegar
For instance, increased VDR affinity to 1,25(OH)2D3 or greater VDR activity for a given amount of 25(OH)D may protect against low levels of 25(OH)D; a situation which may be observed among high-latitude residents (69). The expression of CYP27B1 and CYP24A1, involving in vitamin D metabolism, are regulated through VDR-mediated transcriptional mechanisms (70,71); hence, vitamin D-mediated gene expression could be altered through differential activity of the VDR (69). The expression of CYP24A1 is upregulated in response to high levels 1,25(OH)2D while low levels of 1,25(OH)2D induce expression of the CYP27B1 through ligand (1,25(OH)2D) mediated VDR transcription (52,71). This homeostasis may impair in some subgroup; for instance, a specific SNP may decrease the efficiency of CYP27B1 gene resulting in elevated circulating 25(OH)D levels but decreased intracellular 1,25(OH)2D concentration which could predispose people to adverse health effects of vitamin D deficiency despite higher circulating 25(OH)D concentration (72). Therefore, SNPs in the VDR gene may affect the activity of CYP24A1, resulting in the overall inter-personal variation of circulating vitamin D metabolites (70).
Effects of 1,25 and 24,25 Vitamin D on Corneal Fibroblast VDR and Vitamin D Metabolizing and Catabolizing Enzymes
Published in Current Eye Research, 2021
Xiaowen Lu, Zhong Chen, Mitchell A. Watsky
Renal CYP27B1 is responsible for generating circulating levels of active 1,25-Vit D3 and is also widely distributed in other organs, including dendritic cells, parathyroid cells, osteoblasts, osteoclasts, keratinocyte, mammary epithelial cells, renal tubular cells, pancreatic beta cells, vascular endothelial cells, and prostate epithelial cells.21,36 CYP24A1 plays an important role in the regulation of vitamin D action and reduces the pool of 25-Vit D3 available for 1α-hydroxylation. Mutations of CYP27B1 result in the lack of 1,25-Vit D3 synthesis, whereas mutations of CYP24A1 lead to excess 1,25-Vit D3.20 In the corneal epithelium, 1,25-Vit D3 and 24,25-Vit D3 stimulate CYP24A1 in a VDR-dependent manner, while 24,25-Vit D3 stimulates CYP27B1 via a VDR independent pathway.3 However, the effects of vitamin D on corneal fibroblasts are uncertain, and the control and feedback pathways of vitamin D metabolism in corneal fibroblasts are unclear.