Calcitonin selectively stimulates 25-hydroxyvitamin D3-1α-hydroxylase in proximal straight tubule of rat kidney

Kawashima, Hiroyuki; Torikai, Shozo; Kurokawa, Kiyoshi

doi:10.1038/291327a0

Cited by 157 publications

(60 citation statements)

References 13 publications

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“…3, we detected ␤-galactosidase activity in the renal cortex only. This observation is consistent with previous studies of isolated nephrons from vitamin D-deficient rats, chickens, and rabbits, all of which reported localization of 1␣-hydroxylase activity to the proximal tubules (52)(53)(54)(55). Given the extensive staining of the distal nephrons reported by Hewison and coworkers (28), our reporter assay system should have easily detected 1␣-hydroxylase promoter activity in the renal medulla.…”

Section: Discussionsupporting

confidence: 80%

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vanhooke

Prahl

Kimmel-Jehan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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. The second hydroxylation is catalyzed by the 25-hydroxyvitamin D 3 -1␣-hydroxylase (1␣-hydroxylase), a mitochondrial cytochrome P450 enzyme that is the product of the CYP27B1 gene (2-6). Activity of 1␣-hydroxylase is tightly regulated through complex mechanisms that depend on the circulating levels of calcium, phosphorus, parathyroid hormone, and 1,25(OH) 2 D 3 .Mutations in the 1␣-hydroxylase gene are known to cause vitamin D-dependency rickets type I (VDDR-I) (2, 7-9). Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10). VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.The experiments reported by Fraser and Kodicek in 1970 (12) were the first to demonstrate the kidney as the major, if not the only, tissue in which 1,25(OH) 2 D 3 is produced under normal physiological conditions. Over the next several years, extrarenal production of 1,25(OH) 2 D 3 was convincingly demonstrated in pregnant nephrectomized rats and in an anephric patient suffering from sarcoidosis (13-15). In these cases, synthesis was localized to the placenta and the sarcoid macrophages (14,16,17). Production of 1,25(OH) 2 D 3 at other sites has remained a subject of much investigation. A number of research groups have reported 1␣-hydroxylase activity in cultured cells, including those of the skin, bone, cartilage, intestine, prostate, and vascular epithelium (18 -25). Bikle et al. (26) have also reported 1,25(OH) 2 D 3 production in perfused flaps of porcine skin. Local production of 1,25(OH) 2 D 3 has been proposed to regulate cellular function and͞or differentiation in an autocrine or paracrine fashion (18,19,24,27,28), and it has been suggested that keratinocytes could supply 1,25(OH) 2 D 3 to the systemic circulation when renal production of the hormone is impaired (26,29). Production of extrarenal 1,25(OH) 2 D 3 in these experiments is not supported, however, by in vivo metabolic studies in nephrectomized nonpregnant rats. In these studies, two independent research groups were unable to detect 3 H-1,25(OH) 2 D 3 in the tissue or plasma after administering a dose of 3 H-25-OH-D 3 of high specific radioactivity (30,31). These conflicting results demonstrate a need for further investigation of the in vivo expression of the 1␣-hydroxylase. We have approached such an investigation by using gene targeting to replace the 1␣-hydroxylase coding sequence with a bacterial lacZ gene controlled by the 1␣-hydroxylase promoter. The lacZ gene codes for ␤-galactosidase, whose activity is readily detected in situ through histochemical staining with X-Gal (32). Herein we report the successful production of 1␣-hydroxylase null mice harboring the lacZ gene and present our analysis of in vivo 1␣-hydroxylase...

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Section: Discussionsupporting

confidence: 80%

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vanhooke

Prahl

Kimmel-Jehan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies of Kawashima et al (11,12,20) and Akiba et al (10) have established the presence oftwo distinct 25(OH)D-lIa-hydroxylase systems in the mammalian kidney. Using microdissected nephron segments from rat and fetal rabbit kidney, these investigators localized enzyme activity in the PCT and PST.…”

Section: Discussionmentioning

confidence: 99%

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Nesbitt¹,

Lobaugh²,

Drezner³

1987

J. Clin. Invest.

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“…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). Biochemical investigations showed that the enzyme involved was a mixedfunction oxidase with a cytochrome P450 component ( 68 ).…”

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

confidence: 99%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

395

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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Calcitonin selectively stimulates 25-hydroxyvitamin D3-1α-hydroxylase in proximal straight tubule of rat kidney

Cited by 157 publications

References 13 publications

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Cytochrome P450-mediated metabolism of vitamin D

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Calcitonin selectively stimulates 25-hydroxyvitamin D3-1α-hydroxylase in proximal straight tubule of rat kidney

Cited by 157 publications

References 13 publications

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Cytochrome P450-mediated metabolism of vitamin D

Contact Info

Product

Resources

About

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin