Assay and properties of rat yolk sac 25-hydroxyvitamin D3 1.alpha.-hydroxylase

Paulson, Susan K.; Phelps, Mary; DeLuca, Hector F.

doi:10.1021/bi00370a014

Cited by 9 publications

(4 citation statements)

References 36 publications

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“…1 α-hydroxylase, also a part of the cytochrome P450 complex (CYP27B1), is the rate-limiting enzyme located in the inner membrane of the mitochondria, and functions as a mixed-function oxidase. 68,69 Although, predominantly expressed in the proximal renal tubules, its activity has been detected in the distal nephron 70 as well as in extrarenal tissues including monocytes, 71 keratinocytes, 72 colon, lung, and parathyroid cells. 73,74 It is worth noting that, while the renal 1 α-hydroxylase performs endocrine functions, the extrarenal 1 α-hydroxylase principally acts in an autocrine or paracrine fashion with cell-specific functions.…”

Section: Discussionmentioning

confidence: 99%

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Annamalai

Ganesh

Viswanathan

2020

Exp Biol Med (Maywood)

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Acute kidney injury causes significant morbidity and mortality. This experimental animal study investigated the simultaneous impact of iron and vitamin D on acute kidney injury induced by iohexol, an iodinated, non-ionic monomeric radiocontrast agent in Wistar rats. Out of 36 healthy male Wistar rats, saline was injected into six control rats (group 1) and iohexol into the remaining 30 experimental rats (groups 2 to 6 comprising six rats each). Biochemical, renal histological changes, and gene expression of iron-regulating proteins and 1 α-hydroxylase were analyzed. Urinary neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, urine protein, serum and urine catalytic iron, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and tissue lipid peroxidation were assayed. Rats injected with iohexol showed elevated urinary NGAL (11.94 ± 6.79 ng/mL), serum creatinine (2.92 ± 0.91 mg/dL), and urinary protein levels (11.03 ± 9.68 mg/mg creatinine) together with histological evidence of tubular injury and iron accumulation. Gene expression of iron-regulating proteins and 1 α-hydroxylase was altered. Serum and urine catalytic iron levels were elevated (0.57 ± 0.17; 48.95 ± 29.13 µmol/L) compared to controls (0.49 ± 0.04; 20.7 ± 2.62 µmol/L, P < 0.001). Urine catalytic iron positively correlated with tissue peroxidation (r = 0.469, CI 0.122 to 0.667, P = 0.004) and urinary NGAL (r = 0.788, CI 0.620 to 0.887, P < 0.001). 25-hydroxyvitamin D3 (61.58 ± 9.60 ng/mL) and 1,25-dihydroxyvitamin D3 (50.44 ± 19.76 pg/mL) levels increased simultaneously. In a multivariate linear regression analysis, serum iron, urine catalytic iron, and tissue lipid peroxidation independently and positively predicted urinary NGAL, an acute kidney injury biomarker. This study highlights the nephrotoxic potential of catalytic iron besides demonstrating a concurrent induction of vitamin D endogenously for possible renoprotection in acute kidney injury. Impact statement This work provides in-depth insights on catalytic iron-induced cytotoxicity and the resultant triggering of endogenous vitamin D synthesis in experimental acute kidney injury. Our results reveal significantly elevated levels of catalytic iron culminating in oxidant-mediated renal injury and a concomitant increase in 1,25-dihdyroxyvitamin D3 levels. Also, changes in other iron-related proteins including transferrin, ferritin, and hepcidin were observed both in the serum as well as in their mRNA expression. We consider all these findings vital since no connection between catalytic iron and vitamin D has been established so far. Furthermore, we believe that this work provides new and interesting results, with catalytic iron emerging as an important target in ameliorating renal cellular injury, possibly by timely administration of vitamin D. It also needs to be seen if these observations made in rats could be translated to humans by means of robust clinical trials.

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Section: Discussionmentioning

confidence: 99%

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Annamalai

Ganesh

Viswanathan

2020

Exp Biol Med (Maywood)

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“…Every definitive study to date has localized the lahydroxylase to the mitochondria (10,11,40). One exception to this was a study by Paulson et al (44), which described a purported 25(OH)D3 la-hydroxylase to be localized in microsomes of the rat yolk sac. They also reported in the study that the purported microsomal la-hydroxylase was totally inhibited by N,N'-diphenyl-p-phenylenediamine (DPPD), a free radical scavenger that is sometimes used as an antioxidant (45).…”

Section: Identificationmentioning

confidence: 99%

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

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

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In vitro studies were performed to assess the ability of hepatic homogenates, mitochondria, and microsomes to la-hydroxylate 25-hydroxyvitamin D3 (25(OH)D3]. Addition of 25(OH)D3 to either hepatic mitochondria or microsomes caused a concentration-dependent increase in the production of 1,25-dihydroxyvitamin D3 [1,25(OH) Because of its inability to achieve substrate saturation, meaningful kinetic parameters could not be calculated for the hepatic microsomal la-hydroxylase. These data demonstrate the liver to be an even more dynamic organ than was previously believed with respect to vitamin D metabolism in that the liver has the potential to produce 1,25(OH)2D3 in situ by at least two separate mechanisms.It is well established that various side chain and/or A-ring hydroxylation reactions are essential for the metabolic activation of vitamin D3 (1, 2). Circulating vitamin D3 first undergoes a hepatic conversion to 25-hydroxyvitamin D3 [25(OH)D3] (3). The hydroxylase enzymes responsible for this conversion are known to be cytochrome P-450 mixed-function oxidases that are NADPH dependent and are located in both hepatic mitochondria (4-6) and microsomes (7,8). Final activation of 25(OH)D3 into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] takes place primarily in the kidney (9). The renal enzyme responsible for this activation, 25(OH)D3 lahydroxylase, is also known to be a cytochrome P450 mixedfunction oxidase that is located solely in the inner mitochondrial membrane (10, 11). In recent years, other tissues have also been shown to be capable of synthesizing 1,25(OH)2D3, including placenta (12), bone cells (13), lymphatic tissue (14), and keratinocytes (15). Compared with the renal 25(OH)D3 la-hydroxylase, very little information is known with respect to the metabolic control of these extrarenal 25(OH)D3 lahydroxylases and essentially no information is available concerning their subcellular distribution.Because of the important role of 1,25(OH)2D3 in various aspects of hepatic function (16-24), the possibility that the liver could synthesize in situ this hormonal form of vitamin D3 was investigated. It is reported here that both hepatic mitochondria and microsomes possess a 25(OH)D3 lahydroxylase in significant amounts. These enzymes differ in some characteristics, but both appear to behave as cytochrome P-450 mixed-function oxidases. MN). Coomassie blue protein assay reagent was purchased from Pierce. Nicotinamide adenine dinucleotide phosphate, isocitrate, N,N'-diphenylethylenediamine (DPED), dithiothreitol, and ethylenediaminetetraacetic acid were purchased from Sigma. All solvents were of HPLC grade and were obtained from Fisher. MATERIALS AND METHODS ReagentsLivers. Livers from 3-month-old castrated male pigs, maintained on stock diet, were obtained at the time of slaughter. The livers were perfused with ice-cold 0.15 M NaCl, minced, and placed in an appropriate volume of ice-cold 50 mM Na2HPO4 (pH 7.4) buffer containing 0.25 M sucrose and 0.5 mM EDTA to provide a 20% (wt/vol) 6009The publication costs of th...

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“…Furthermore, low Vitamin D levels have been reported to increase the risk for type 1 diabetes mellitus [10] and Vitamin D supplementation to reduce it. CYP27B1 (25-hydroxyvitamin D 3 -1␣-hydroxylase) is a mitochondrial P450 enzyme [11], which catalyzes the metabolization of 25-hydroxyvitamin D 3 to 1,25(OH) 2 D 3 . It is the key enzyme determining the rate of 1,25(OH) 2 D 3 production.…”

Section: Introductionmentioning

confidence: 99%

CYP27B1 polymorphisms variants are associated with type 1 diabetes mellitus in Germans

López

Regulla

Pani

et al. 2004

The Journal of Steroid Biochemistry and Molecular Biology

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Assay and properties of rat yolk sac 25-hydroxyvitamin D3 1.alpha.-hydroxylase

Cited by 9 publications

References 36 publications

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

CYP27B1 polymorphisms variants are associated with type 1 diabetes mellitus in Germans

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