25-hydroxyvitamin D3 metabolism by isolated perfused rat kidney

Rosenthal, A.; Jones, Glenville; Kooh, Sang Whay; Fraser, Donald R.

doi:10.1152/ajpendo.1980.239.1.e12

Cited by 17 publications

(24 citation statements)

References 16 publications

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“…In the intact, vitamin D-replete kidney, synthesis of 24,25(OH)2D3 is the major pathway for 25(OH)D3 metabolism (46). In vitro administration of exogenous 1,25(OH)~D3 in a dose-dependent fashion increases recovery of 24,25(OH)zD3 and decreases recovery of 1,25(OH)zD3 in kidney (25, 26) and in extrarenal sites of 1,25(OH)2D3 synthesis (47,48).…”

Section: Discussionmentioning

confidence: 99%

Evidence for Human Placental Synthesis of 24,25-Dihydroxyvitamin D3 and 23,25-Dihydroxyvitamin D3

et al. 1993

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In birds and mammals, vitamin D3 is 25-hydroxylated in the 24,25(OH)2D3 was identified by cochromatography with liver and converted to the prohormone 25(OH)D3, which underauthentic standard on four different HPLC systems, scan-goes further hydroxylation steps principally in the kidney. The ning UV spectrophotometry profile of the metabolite, sen-two major dihydroxylated metabolites produced in the kidney sitivity to periodate cleavage, and mass spectrometry of are 1,25(OH)zD3, which is the hormonal form of the vitamin (I), the putative placental 24,25(OH)2D3 and its periodate and 24,25(OH)2D3 (2, 3), a putative regulator of developmental cleavage product. We also identified for the first time bone formation (4-13). The biologic roles of the other known placental synthesis of 23,25(OH)2D3 using cochromatog-natural dihydroxylated vitamin D3 metabolites, 23,25(OH)2D3 raphy with authentic standard on two different HPLC and 26,25(OH)2D3, are not well understood. systems, scanning UV spectrophotometry, resistance toThe observation that nephrectomized, vitamin D3-deficient periodate cleavage, and mass spectrometry. When troph-pregnant rats retain the ability to convert ['H]25(OH)D3 to [3H] oblast was incubated for up to 4 h with physiologic concen-1,25(OH)2D3 in vivo (14, 15) (17) and human (18-22) placenta or incubated trophoblast with supraphysiologic concentra-decidua. In contrast to placental la-hydroxylation, 24R-hydroxtions of 25(OH)D3 (6-10 pM), both 24,25(OH)2D3 and ylation of 25(OH)D3 has not been thoroughly investigated. Sev-1,25(OH)2D3 were synthesized. These results provide un-eral reports have identified placenta as a possible site for 24-equivocal evidence for placental synthesis of both hydroxylation (16, 18-21), but none of these studies character-24,25(OH)2D3 and 23,25(OH)2D3. These findings also sug-ized the putative placental 24,25(OH)2D3 through more extensive gest that supraphysiologic substrate concentrations satu-chromatographic analysis or by mass spectrometry. Moreover, rate the placental 24-hydroxylase and may permit accu-recently Hollis et al. (22) failed to demonstrate any 24,25(OH)2D3 mulation of placental 1,25(OH)2D3 by preventing its fur-production by either human placental homogenates or subcelther metabolism. Consequently, the identification of this lular fractions, despite evidence for l,25(OH)2D3 production in high basal 24-hydroxylase activity in trophoblast may these preparations. These inconsistencies among previous reports explain inconsistencies among previous reports regarding prompted us to investigate whether placenta might possess a placental 1,25(OH)2D3 production. We speculate that ac-biologically important 25(OH)D3-24-hydroxylation pathway. tive placental 24-hydroxylation may serve important func-Like kidney, placenta apparently synthesizes 1,25(OH)2D3 and tions in perinatal vitamin D metabolism. (Pediatr Res 34: expresses 1,25(OH)zD3 receptors (23). In kidney, 24R-and la-98-104,1993) hydroxylase activities are regulated in a reciprocal fashion (24-26); 1,25(OH)2D...

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Section: Discussionmentioning

confidence: 99%

Evidence for Human Placental Synthesis of 24,25-Dihydroxyvitamin D3 and 23,25-Dihydroxyvitamin D3

et al. 1993

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“…Recently, several investigators were able to determine the la-hydroxylase activity of the mammalian kidney in vitro by using the mitochondrial fraction, homogenates, isolated kidney cells, and isolated perfused kidney (17)(18)(19)(20). In contrast to these previous methods, a use of microdissected, welldefined nephron segments to measure la-hydroxylase and 24-Proc.…”

Section: Discussionmentioning

confidence: 99%

Localization of 25-hydroxyvitamin D3 1 alpha-hydroxylase and 24-hydroxylase along the rat nephron.

Kawashima¹,

Torikai²,

Kurokawa³

1981

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

166

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Defined nephron segments were microdissected from the kidney of vitamin D-deficient rats, normal rats, and normal rats treated with la,25-dihydroxyvitamin D3 [la,25-(OH)2D3]. Tubule segments were incubated with 3H-labeled 25-hydroxyvitamin D3 and the rates of production of 3H-labeled la,25-(QH) 2D3 and 24,25-dihydroxyvitamin D3 [24, The use of defined nephron segments may be useful for stucly of the distribution and regulation of 25-hydroxyvitamin D3 hydroxylases in the kidney.It is well established that vitamin D3 must undergo sequential hydroxylations, first in the liver to 25-hydroxyvitamin D3 (25-OH-D3) and then in the kidney to either la,25-dihydroxyvitamin D3 [1a,25-(OH)2D3] or 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] before it exerts its biological actions (1). Under normal physiological conditions, the kidney is believed to be the principal site of synthesis of 1a,25-(OH)2D3 which is thought to be the primary hormonal form of vitamin D3 (1). The kidney seems also to be the major site of 24,25-(OH)2D3 production because plasma levels of 24,25-(OH)2D3 are markedly decreased in anephric patients and rats (2, 3). The activities of 25-(OH)D3 la-and 24-hydroxylase, the enzymes responsible for the production of la,25-(OH)2D3 and 24,25-(OH)2D3, respectively, are finely regulated by various ions and hormones, including calcium, phosphate, parathyroid hormone, and vitamin D; in general, there are reciprocal changes in the activities of these two enzymes (1).Recent studies have demonstrated the exclusive localization of la-hydroxylase in the proximal tubules in chicken and fetal rabbit kidneys (4, 5). However, the precise location of la-hydroxylase in the mature mammalian kidney is not known. Furthermore, the location of 24-hydroxylase in the kidney has not been studied. Determination of the precise location of both cahydroxylase and 24-hydroxylase in the kidney may provide fur, ther insight into the regulatory mechanisms of these two hydroxylase systems.Using single nephron segments microdissected from rats, we found that both la-hydroxylase and 24-hydroxylase are located only in the proximal convoluted tubules (PCT) of vitamin Ddeficient and normal rats, respectively, and that 24-hydroxylase is present in both the PCT and proximal straight tubules (PST) in normal rats treated with la,25-(OH)2D3.MATERIALS AND METHODS Animals. To create vitamin D deficiency, male Holtzman rats were fed a vitamin D-deficient diet, containing 0.45% calcium and 0.3% phosphorus, for 7-10 weeks after weaning (6). The mean (±SEM) plasma concentrations of calcium and inorganic phosphate in vitamin D-deficient rats at the time of study were 4.4 ± 0.5 and 4.8 ± 0.5 mg/100 ml, respectively. Normal male rats (Holtzman or Wistar) weighing 200-300 g were fed a laboratory rat chow; some were given daily subcutaneous injections of la,25-(OH)2D3 (25 ng/kg) for 3-10 days. Mean (±SEM) plasma concentrations of calcium and inorganic phosphate in normal rats were 9.9 ± 0.1 and 6.7 ± 0.3 mg/100 ml, respectively; in rats treated with la,25-(O...

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“…The mechanism that the factors that upregulate one enzyme downregulate the other. This is evident in the isolated perfused kidney from the rat fed a low-calcium vitamin D-defi cient diet or a low-PO 4 vitamin D-defi cient diet, which is in the 1 ␣ -hydroxylation mode and which over a 4 h perfusion period after being exposed to its 25-OH-D 3 substrate, turns off CYP27B1 expression and 1 ␣ -hydroxylation and turns on CYP24A1 and 24-hydroxylation ( 111 ). The vitamin D metabolic system seems ideally designed to avoid synthesis of excessive amounts of the hormone and also to degrade the hormone, or even its substrate, by superinduction of catabolic processes, including CYP24A1.…”

Section: Other Potential 25-hydroxylasesmentioning

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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25-hydroxyvitamin D3 metabolism by isolated perfused rat kidney

Cited by 17 publications

References 16 publications

Evidence for Human Placental Synthesis of 24,25-Dihydroxyvitamin D3 and 23,25-Dihydroxyvitamin D3

Evidence for Human Placental Synthesis of 24,25-Dihydroxyvitamin D3 and 23,25-Dihydroxyvitamin D3

Localization of 25-hydroxyvitamin D3 1 alpha-hydroxylase and 24-hydroxylase along the rat nephron.

Cytochrome P450-mediated metabolism of vitamin D

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