1alpha-Hydroxylase and the action of vitamin D

Hewison, Martin; Zehnder, Daniel; Bland, Rosemary; Stewart, PM

doi:10.1677/jme.0.0250141

Cited by 196 publications

(135 citation statements)

References 23 publications

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“…1a-Hydroxylase has been cloned (33)(34)(35), and studies of the molecular mechanisms involved in its regulation demonstrated that administration of PTH and calcitonin, restriction of dietary calcium, and vitamin D deficiency are able to increase 1a-hydroxylase mRNA expression. On the other hand, administration of 1,25(OH) 2 D results in a decrease in 1a-hydroxylase expression and prevents the increased expression induced by PTH and calcitonin (36). In our study, the increased 1a-hydroxylase activity in PH patients could be related to elevated PTH serum levels, as described previously (24).…”

Section: Resultssupporting

confidence: 81%

Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

Bevilacqua

Invernizzi

Righini³

et al. 2011

European Journal of Endocrinology

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Context: In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 mg/day) increases the serum levels of both 25(OH)D and 1,25(OH) 2 D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH). Objective: To evaluate the different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls. Design: We evaluated the main physiological regulators of 1a-hydroxylase and the substrate-product relationship of 25(OH)D and 1,25(OH) 2 D in 20 patients with PH, 25 with FBH, and 122 healthy sex-and age-matched controls before and after administration of 25(OH)D for 2 weeks. Results: 25(OH)D increased significantly in all subjects, whereas 1,25(OH) 2 D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate-product relationship of 25(OH)D-1,25(OH) 2 D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups. Conclusions: The lack of 1,25(OH) 2 D increase in FBH may be due to a direct inhibitory effect on 1a-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH) 2 D, or a decreased stimulus of 1a-hydroxylase related to persistently low levels of hCT.

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Section: Resultssupporting

confidence: 81%

Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

Bevilacqua

Invernizzi

Righini³

et al. 2011

European Journal of Endocrinology

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“…However, 1-␣-hydroxylase is present in other sites within the kidney, such as the distal tubules and collecting ducts. 49,50 Perhaps most curious is the observation that 1-␣-hydroxylase is induced by LPS in the distal nephron, as studied in cell culture. 51 This leads to the possibility that, as in other settings, calcitriol might be utilized to regulate innate immune defenses in the kidney.…”

Section: A Simplified Picture Of the Innate Host Defenses In The Urinmentioning

confidence: 99%

Antimicrobial Peptides, Innate Immunity, and the Normally Sterile Urinary Tract

Zasloff¹

2007

Journal of the American Society of Nephrology

191

169

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Considering the anatomical location of the urethral meatus, it is surprising that urine is normally sterile. The defensive properties of uroepithelia help maintain this sterility as strategically necessary for long-term survival. Epithelia lining the urinary tract prevent adhesion of bacteria by release of Tamm-Horsfall protein, lactoferrin, lipocalin, and constitutive and inducible bactericidal antimicrobial peptides such as ␣-and ␤-defensins and cathelicidin. Microbes that overwhelm these early defenses contact uroepithelia and activate an innate immune response through Toll-like receptor 4. With persistence of increasing numbers of microbes, chemokines (IL-8) and cytokines (IL-1 and TNF␣) attract and activate large numbers of neutrophils and macrophages that damage tubulointerstitial parenchyma. The risk of serious infection in humans seems quite variable. Cathelicidin, for example, is a vitamin D-dependent gene, and vitamin D stores may influence susceptibility to urinary tract infection in selected individuals. As more knowledge accrues, vitamin D supplementation may someday be useful as adjuvant therapy in this setting.

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“…The importance of 1,25(OH) 2 D 3 as a pleiotropic modulator of tissue functions is strengthened by the presence of key components of vitamin D metabolism at different sites. The cognate nuclear receptor for 1,25(OH) 2 D 3 (VDR) is ubiquitous in proliferating cells (Hewison et al 2000) and the mitochondrial cytocrome P450 enzyme 25-hydroxyvitamin D 3 -1 -hydroxylase (1 -OHase), which catalyzes the synthesis of 1,25(OH) 2 D 3 from its precursor 25-hydroxyvitamin D 3 , is expressed in the kidney and in several extrarenal tissues (Zehnder et al 2001(Zehnder et al , 2002b. The widespread co-expression of VDR and 1 -OHase emphasizes a putative role for 1,25(OH) 2 D 3 as an autocrine/paracrine agent with diverse physiological functions (Hewison et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

Viganò

Lattuada

Mangioni

et al. 2006

Journal of Molecular Endocrinology

165

110

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In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), has potent anti-proliferative/immunomodulatory effects on various tissues. Consistently, the enzyme that catalyzes the synthesis of 1,25(OH) 2 D 3 , 1 -hydroxylase (1 -OHase) and the vitamin D receptor have a widespread tissue distribution. Among site-specific functions, the hormone has been suggested to be involved in uterine physiology. However, molecular analysis of the vitamin D system in normal endometrium throughout the menstrual cycle as well as its regulation in the context of endometrial physiological and pathological events have received very limited attention. Thus, we have studied expression, localization and regulation of 1 -OHase in human cycling and early pregnant endometrium. The capacity for 1 -hydroxylation and the presence of vitamin D receptor in endometrial cells have also been evaluated. The functional significance of these findings has been tested by evaluating gene expression of the catabolic enzyme, vitamin D 24-hydroxylase, and of the adhesion protein, osteopontin. Finally, to verify any potential dysfunction of the vitamin D system in endometriosis, a reproductive disease characterized by immune-mediated anomalies, we have analyzed expression of 1 -OHase in both eutopic and ectopic endometrium of affected patients. Results obtained showed that the active form of the 1 -OHase gene was expressed in human endometrial stromal cells independent of the cycle phase but with a significant increase in early pregnant decidua. A similar profile was observed for the protein, which was abundantly expressed in the cytoplasm of both endometrial stroma and epithelial glands. Both cycling and early pregnant endometrial cells also expressed the vitamin D receptor. In the same cells, 1 -OHase mRNA levels were significantly stimulated by the pro-inflammatory cytokine interleukin (IL)-1 (50 and 500 pg/ml) while addition of the active form of the hormone could modulate both CYP24 and osteopontin gene expression. The 1 -OHase gene was also expressed in ectopic endometrium and its levels were increased in proliferative phase cultures derived from patients with endometriosis. Human cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D. The IL-1 −mediated induction of 1 -OHase gene and the hormonal modulation of osteopontin support a role for the hormone in the immunological mechanisms underlying uterine function. Abnormalities of this system are present in endometriosis.

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1alpha-Hydroxylase and the action of vitamin D

Cited by 196 publications

References 23 publications

Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

Antimicrobial Peptides, Innate Immunity, and the Normally Sterile Urinary Tract

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

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