Extrarenal 1α-Hydroxylase

Hewison, Martin; Adams, John S.

doi:10.1016/b978-0-12-381978-9.10045-9

Cited by 21 publications

(20 citation statements)

References 288 publications

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“…Using similar techniques, several groups reported low but detectable expression of CYP27B1 in a variety of cultured cell lines (e.g., prostate and colonic cells) (96)(97)(98). Immunohistochemistry data from analysis of animal and human tissues has revealed the presence of the CYP27B1 protein in several tissues purported to express 1 ␣ -hydroxylase activity (e.g., skin, colon, macrophage, prostate, breast) ( 4,78 ). Not all studies have supported the conclusion that CYP27B1 is expressed outside of the kidney in normal, nonpregnant animals.…”

Section: Other Potential 25-hydroxylasesmentioning

confidence: 99%

“…Although many of these groups used kidney libraries as the source of the enzyme, interestingly, other groups reported fi nding the same CYP27B1mRNA in keratinocyte ( 76 ) and human colonic cell HT-29 ( 77 ) libraries, suggesting that the enzyme was identical in all locations. Subsequently, it has been confi rmed that the CYP27B1 protein is identical in all locations ( 4,78 ), whether renal or extrarenal, although the regulation in these different tissue locations must involve different hormones and effectors.…”

Section: -Hydroxyvitamin D-1 ␣ -Hydroxylase (Cyp27b1)mentioning

confidence: 99%

“…The need to defi ne the enzyme in biochemical terms became urgent as soon as it became apparent that the 25-hydroxyvitamin D-1 ␣ -hydroxylase was a central regulatory axis of the calcium and phosphate homeostatic systems, subject to upregulation by parathyroid hormone (PTH), low Ca 2+ , and low PO 4 3-levels ( 1,61,62 ). It was quickly recognized that serum 1,25-(OH) 2 D 3 was predominantly made in the kidney ( 3,63 ), with a PTH-regulated form located in the proximal convoluted tubule and a calcitonin-regulated form in the proximal straight tubule (64)(65)(66)(67).…”

Section: -Hydroxyvitamin D-1 ␣ -Hydroxylase (Cyp27b1)mentioning

confidence: 99%

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Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

388

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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Section: Other Potential 25-hydroxylasesmentioning

confidence: 99%

Section: -Hydroxyvitamin D-1 ␣ -Hydroxylase (Cyp27b1)mentioning

confidence: 99%

Section: -Hydroxyvitamin D-1 ␣ -Hydroxylase (Cyp27b1)mentioning

confidence: 99%

See 1 more Smart Citation

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

388

292

View full text Add to dashboard Cite

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“…Conversion of 25(OH)D 3 , the circulating prohormone, to 1,25(OH) 2 D 3 is subsequently accomplished in the kidney in a tightly controlled enzymatic step catalyzed by 1␣-hydroxylase (CYP27B1) (16). However, normal and malignant colon, prostate and breast cells also express CYP27B1 that is not tightly regulated and thus circulating 25(OH)D levels determine the extent of 1,25(OH) 2 D that can be synthesized locally within these tissues (22). These observations provide a rationale for vitamin D 3 to exhibit all of the anticancer actions of administered calcitriol and thereby also provide a basis for the protective effect of sunlight and dietary vitamin D against cancer development.…”

mentioning

confidence: 99%

Dietary Vitamin D3 and 1,25-Dihydroxyvitamin D3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer

Swami¹,

Krishnan²,

Wang³

et al. 2012

Endocrinology

143

101

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1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D(3). Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

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“…It has been detected in chondrocytes, osteoblasts, keratinocytes, macrophages, monocytes, placenta decidual cells, vasculature endothelial cells, enterocytes and pancreas islets. 47 This array of sites suggests that calcitriol may have important autocrine and paracrine roles in various physiological functions, and there is a growing body of information along those lines. It can be assumed that in PDDR both systemic and local production of calcitriol is disrupted by the CYP27B1 mutations.…”

Section: Pseudo-vitamin D Deficiency Ricketsmentioning

confidence: 99%

Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets

Glorieux

Pettifor

2014

BoneKEy Reports

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This review describes the pathogenesis, clinical presentation and biochemical perturbations found in privational (nutritional) rickets and pseudo-vitamin D deficiency rickets (PDDR), an autosomal recessive condition with loss of function mutations in CYP27B1. It may seem strange to combine a discussion on privational rickets and PDDR as a single topic, but privational rickets and PDDR present with similar clinical signs and symptoms and with similar perturbations in bone and mineral metabolism. Of interest is the characteristic lack of features of rickets at birth in infants with PDDR, a finding which has also been reported in infants born to vitamin D-deficient mothers. This highlights the independence of the fetus and neonate from the need for vitamin D to maintain calcium homeostasis during this period. The variable roles of vitamin D deficiency and dietary calcium deficiency in the pathogenesis of privational rickets are discussed and the associated alterations in vitamin D metabolism highlighted. Although PDDR is a rare autosomal recessive disorder, results of long-term follow-up are now available on the effect of treatment with calcitriol, and these are discussed. Areas of uncertainty, such as should affected mothers breastfeed their infants, are emphasized.

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Extrarenal 1α-Hydroxylase

Cited by 21 publications

References 288 publications

Cytochrome P450-mediated metabolism of vitamin D

Cytochrome P450-mediated metabolism of vitamin D

Dietary Vitamin D3 and 1,25-Dihydroxyvitamin D3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer

Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets

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