Altered Pharmacokinetics of 1α,25-Dihydroxyvitamin D3and 25-Hydroxyvitamin D3in the Blood and Tissues of the 25-Hydroxyvitamin D-24-Hydroxylase (Cyp24a1) Null Mouse

Masuda, Sonoko; Byford, Valarie; Arabian, Alice; Sakai, Yoshiyuki; Demay, Marie B.; St‐Arnaud, René; Jones, Glenville

doi:10.1210/en.2004-1116

Cited by 164 publications

(94 citation statements)

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“…vitro studies collectively showed that calcitroic acid and 1␣,25-(OH) 2 D 3 -26,23-lactone are both 1␣,25-(OH) 2 D 3 -induced products, both result from recombinant CYP24A1 action, and both are absent in VDR-null and CYP24A1-null mice in vivo (8,9). These products are physiologically different because the calcitroic acid is a rapidly cleared catabolite with no discernible biological activity and 1␣,25-(OH) 2 D 3 -26,23-lactone belongs to a family of known VDR antagonists (14,15) with better vitamin D-binding protein-binding properties and greater metabolic stability (26).…”

Section: Discussionmentioning

confidence: 99%

“…1). Studies using CYP24A1-knockout (8) and VDR-knockout mice (8,9) demonstrate the total absence of calcitroic acid and 1␣,25-(OH) 2 D 3 -26,23-lactone formation when the vitamin Dinducible, VDR-mediated CYP24A1 is not expressed. The in vivo result of CYP24A1 ablation is decreased viability, with 50% of mice not surviving beyond weaning because of hypercalcemia and nephrocalcinosis (8,10).…”

mentioning

confidence: 99%

“…Studies using CYP24A1-knockout (8) and VDR-knockout mice (8,9) demonstrate the total absence of calcitroic acid and 1␣,25-(OH) 2 D 3 -26,23-lactone formation when the vitamin Dinducible, VDR-mediated CYP24A1 is not expressed. The in vivo result of CYP24A1 ablation is decreased viability, with 50% of mice not surviving beyond weaning because of hypercalcemia and nephrocalcinosis (8,10). Although it has been well established that calcitroic acid is the major biliary product of 1␣,25-(OH) 2 D 3 in the rat (11,12), there have been claims that intermediates of the C24 oxidation pathway retain some biological activity (13) and that the terminal product of 23-hydroxylation, namely 1␣,25-(OH) 2 D 3 -26,23-lactone, belongs to a family of potent VDR antagonists with potential for use in the treatment of Paget's disease (14,15).…”

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Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone

Prosser

Kaufmann

O’Leary

et al. 2007

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

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Studies of 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) have demonstrated that it is a bifunctional enzyme capable of the 24-hydroxylation of 1␣,25-(OH) 2D3, leading to the excretory form, calcitroic acid, and 23-hydroxylation, culminating in 1␣,25-(OH) 2D3-26,23-lactone. The degree to which CYP24A1 performs either 23-or 24-hydroxylation is species-dependent. In this paper, we show that the human enzyme that predominantly 24-hydroxylates its substrate differs from the opossum enzyme that 23-hydroxylates it at only a limited number of amino acid residues. Mutagenesis of the human form at a single substrate-binding residue (A326G) dramatically changes the regioselectivity of the enzyme from a 24-hydroxylase to a 23-hydroxylase, whereas other modifications have no effect. Ala-326 is located in the I-helix, close to the terminus of the docked 25-hydroxylated side chain in a CYP24A1 homology model, a result that we interpret indicates that substitution of a glycine at 326 provides extra space for the side chain of the substrate to move deeper into the pocket and place it in a optimal stereochemical position for 23-hydroxylation. We discuss the physiological ramifications of these results for species possessing the A326G substitution, as well as implications for optimal vitamin D analog design. (Fig. 1). Studies using CYP24A1-knockout (8) and VDR-knockout mice (8, 9) demonstrate the total absence of calcitroic acid and 1␣,25-(OH) 2 D 3 -26,23-lactone formation when the vitamin Dinducible, VDR-mediated CYP24A1 is not expressed. The in vivo result of CYP24A1 ablation is decreased viability, with 50% of mice not surviving beyond weaning because of hypercalcemia and nephrocalcinosis (8, 10). Although it has been well established that calcitroic acid is the major biliary product of 1␣,25-(OH) 2 D 3 in the rat (11, 12), there have been claims that intermediates of the C24 oxidation pathway retain some biological activity (13) and that the terminal product of 23-hydroxylation, namely 1␣,25-(OH) 2 D 3 -26,23-lactone, belongs to a family of potent VDR antagonists with potential for use in the treatment of Paget's disease (14, 15).The degree to which CYP24A1 performs either of these pathways varies with the species. It had been shown in the mid-1980s by using isolated kidney mitochondria from a variety of species, that the 24-hydroxylase and 23-hydroxylase activities copurify (16). Although both pathways are used in humans, certain species, such as the guinea pig (17, 18), were shown to 23-hydroxylate, whereas other species, such as the rat, primarily 24-hydroxylate the substrate, 25-OH-D 3 (16). These studies suggested that the two enzyme activities might have different kinetic parameters, but it was not clear whether the activities resided on a single or distinct polypeptide chains. With the cloning and expression of the recombinant protein from different species (19,20), it became clear that a single polypeptide chain was capable of both C23-and C24-hydroxylation activities (5-7).Recent studies of rat and human CYP24A1 hav...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone

Prosser

Kaufmann

O’Leary

et al. 2007

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

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“…Cyp24a1 KO mice develop hypercalcemia, and 50% of the homozygous mutants die before 3 weeks of age probably due to severe hypercalcemia. The animals surviving to adulthood are fertile despite deposition of mineral in several organs of the mutant mice (Masuda et al 2005). A more detailed evaluation of testis histology and reproductive phenotype were also performed in males from the Tokyo Vdr KO strain, revealing an increased luminal diameter and shortened epithelial width in some tubules from 10-week-old Vdr KO mice compared with controls (Kinuta et al 2000).…”

Section: Vd Regulates Biosynthesis Of Estradiol and Testosteronementioning

confidence: 99%

Vitamin D metabolism, sex hormones, and male reproductive function

Jensen¹

2012

Reproduction

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The spectrum of vitamin D (VD)-mediated effects has expanded in recent years, and VD is now recognized as a versatile signaling molecule rather than being solely a regulator of bone health and calcium homeostasis. One of the recently identified target areas of VD is male reproductive function. The VD receptor (VDR) and the VD metabolizing enzyme expression studies documented the presence of this system in the testes, mature spermatozoa, and ejaculatory tract, suggesting that both systemic and local VD metabolism may influence male reproductive function. However, it is still debated which cell is the main VD target in the testis and to what extent VD is important for sex hormone production and function of spermatozoa. This review summarizes descriptive studies on testicular VD metabolism and spatial distribution of VDR and the VD metabolizing enzymes in the mammalian testes and discusses mechanistic and association studies conducted in animals and humans. The reviewed evidence suggests some effects of VD on estrogen and testosterone biosynthesis and implicates involvement of both systemic and local VD metabolism in the regulation of male fertility potential.

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“…To prevent the excessive accumulation of 1,25(OH) 2 D 3 and its toxic hypercalcemic effects, CYP24 expression is up-regulated by 1,25(OH) 2 D 3 in a negative feedback mechanism (8). CYP24 also catalyzes the removal of 25(OH)D 3 from the body (9).…”

Section: Introductionmentioning

confidence: 99%

Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity

Tan

Dwivedi²,

Anderson³

et al. 2007

Molecular Cancer Therapeutics

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Calcitriol or 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] has antitumor activity and hence its levels in patients may play an important role in disease outcome. Here, we report that the antineoplastic agents, daunorubicin hydrochloride, etoposide, and vincristine sulfate inhibited the ability of 1,25(OH) 2 D 3 to cause the accumulation of mRNA for kidney 25-hydroxyvitamin D 3 24-hydroxylase (CYP24), an enzyme which catabolizes this hormone. This was not due to a drug-induced cytotoxic effect, reduction in the expression of the vitamin D receptor or inhibition of the vitamin D receptor -mediated activation of the mitogen-activated protein kinases or CYP24 promoter activity. Interestingly, there was selective degradation of CYP24 mRNA in the presence of the drugs. This was accompanied by an enhancement in the levels of 1,25(OH) 2 D 3 in cells incubated with 25-hydroxy vitamin D 3 . These data identify a novel mechanism of action of some commonly used antineoplastic agents which by decreasing the stability of CYP24 mRNA would prolong the bioavailability of 1,25(OH) 2 D 3 for anticancer actions. [Mol Cancer Ther 2007;6(12):3131 -8]

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Altered Pharmacokinetics of 1α,25-Dihydroxyvitamin D₃and 25-Hydroxyvitamin D₃in the Blood and Tissues of the 25-Hydroxyvitamin D-24-Hydroxylase (Cyp24a1) Null Mouse

Cited by 164 publications

References 36 publications

Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone

Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone

Vitamin D metabolism, sex hormones, and male reproductive function

Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity

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Altered Pharmacokinetics of 1α,25-Dihydroxyvitamin D3and 25-Hydroxyvitamin D3in the Blood and Tissues of the 25-Hydroxyvitamin D-24-Hydroxylase (Cyp24a1) Null Mouse

Cited by 164 publications

References 36 publications

Single A326G mutation converts human CYP24A1 from 25-OH-D 3 -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) 2 D 3 -26,23-lactone

Single A326G mutation converts human CYP24A1 from 25-OH-D 3 -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) 2 D 3 -26,23-lactone

Vitamin D metabolism, sex hormones, and male reproductive function

Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity

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Altered Pharmacokinetics of 1α,25-Dihydroxyvitamin D₃and 25-Hydroxyvitamin D₃in the Blood and Tissues of the 25-Hydroxyvitamin D-24-Hydroxylase (Cyp24a1) Null Mouse

Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone

Single A326G mutation converts human CYP24A1 from 25-OH-D ₃ -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) ₂ D ₃ -26,23-lactone