Post by Max on Jun 13, 2005 14:18:03 GMT -5
Clinical observations of 1,25-dihydroxyvitamin D in human subjects exposed to (Ro)accutane
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [3].
Interaction with insulin-like growth factor binding proteins (IGFBPs)
Recently, insulin-like growth factor binding proteins (IGFBPs) have been found to be primary mediators of the anti-proliferative actions of the nuclear hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], but dependent on cellular context IGFBPs can also have a mitogenic effect. Expression profiling of all six human IGFBP genes in prostate and bone cancer cells and demonstrated that IGFBP1, 3 and 5 are primary 1alpha,25(OH)2D3 target genes [18].
Vitamin D metabolism
The enzyme 1alpha-hydroxylase, which converts vitamin D to its active form, has been found to be coordinated by Nuclear Factor Kappa B (NFkappaB) [5]. All-trans-retinoic-acid (ATRA) was found to significantly reduce nuclear levels of both subunits (p50 and p65) of NF-kappaB [6]. HB-EGF dramatically suppressed NF-kappaB activity and IL-8 release and decreased NO production in cells pretreated with HB-EGF. HB-EGF blocked NF-kappaB activation by inhibiting IkappaB kinase activation and IkappaB phosphorylation and degradation, thus interfering with NF-kappaB nuclear translocation, DNA-binding activity, and NF-kappaB-dependent transcriptional activity [7]. In cultured keratinocytes, real-time PCR analyses revealed that HB-EGF mRNA expression was elevated dose-dependently with atRA, peaking at 12 h. All-trans retinal and all-trans retinol were found to upregulate HB-EGF when used at 0,1-1,0 microM/l to a similiar extent of all-trans retinoic acid at 1,0-10,0 microM [8]. Cubilin is a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand [13]. In rats, cubilin is a 460-kDa multipurpose, multidomain receptor that contains an NH(2)-terminal 110-residue segment followed by 8 epidermal growth factor (EGF)-like repeats and a contiguous stretch (representing nearly 88% of its mass) [11]. This indicates that a significant upregulation of Heparin binding-EGF may strongly affect cubulin receptors, thus being one pathway of (Ro)accutane inhibition of endocytosis in exposed human subjects. This is further confirmed by the finding that heparin inhibits binding of thyroglobulin to the endocytotic receptor megalin [12] , which also, in a similiar manner binds the plasma carrier for vitamin D, vitamin D binding protein [13].
Inhibition of kidney function of vitamin D-metabolism and endocytosis
In endocytic receptor megalin deficient mice, it has been shown that the 1alpha-hydroxylase can also be coregulated by megalin, and a fall in kidney vitamin D metabolites seems to be accompanied by a raise in TGF-beta1 target genes [9]. Megalin is highly expressed in the proximal tubules of the kidney. This receptor is essential for the renal uptake and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3 [10, 17 and more].
Receptor expression and function
The Vitamin D Receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1alpha,25-dihydroxyvitamin D3 [1]. Receptors bind to hormone response elements (HREs) via their DNA-binding domains (DBDs) [2]. In small doses RARs/RXRs physically interact with Sp1, potentiate Sp1 binding to the GC box motifs [15]. The nucleotide sequence of the Sp1 region is well conserved between the mouse, the human, and the chicken VDR genes, suggesting an important role for these Sp1 sites. Gel shift analysis of the four Sp1 sites of the mVDR promoter has confirmed specific binding complexes to Sp1-1, Sp1-2, and Sp1-4 (Sp1-3 rather binds an unknown complex that is unable to bind the canonical Sp1 GGGGCGGGGC). Deletion or mutation of all the Sp1 sites eliminates promoter activity [16]. It is here suggested that a high dose RA as opposed to a small dose, inhibits Sp1 formation and binding.
The Vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by three base pairs of spacer DNA. Binding of 1alpha,25-dihydroxyvitamin D(3) to the full-length VDR causes destabilization of the VDR homodimer and formation of a heterodimeric complex with the 9-cis retinoic acid receptor (RXR) [2].
Traditional targets for 1alpha,25-dihydroxyvitamin D3 action include tissues involved in the maintenance of calcium homeostasis, bone development and remodeling including the bone, kidney, skeletal and cardiac muscle. PGC-1alpha, a transcriptional coactivator which plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in the kidney, heart, liver and skeletal muscle tissues [1]. The VDR also plays a role in cellular proliferation and differentiation [2]. The 1,25-dihydroxyvitamin D3 receptor (VDR), is also expressed in the human brain, where its function is not clarified, as well as 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents [4]. Down-regulation of 1alpha-hydroxylase promoter through NFkappaB signaling may contribute to the pathogenesis of inflammation-associated osteopenia/osteoporosis [5].
1,25-dihydroxyvitamin D3 (D3) is found accelerate integrin beta 3 transcription [14], signifying that a clinical 1,25-dihydoxyvitamin D3 deficiency likely decreases integrin beta 3 transcription, this due to that the integrin beta 3 is suggested to contain a VDRE.
For further information about VDR receptor expression:
Genecards - VDR
(Genecards database)
GenAtlas - VDR
(GenAtlas database)
For further information about megalin/gp330/LRP-2
Genecards - LRP-2
(Genecards database)
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [3].
Interaction with insulin-like growth factor binding proteins (IGFBPs)
Recently, insulin-like growth factor binding proteins (IGFBPs) have been found to be primary mediators of the anti-proliferative actions of the nuclear hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], but dependent on cellular context IGFBPs can also have a mitogenic effect. Expression profiling of all six human IGFBP genes in prostate and bone cancer cells and demonstrated that IGFBP1, 3 and 5 are primary 1alpha,25(OH)2D3 target genes [18].
Vitamin D metabolism
The enzyme 1alpha-hydroxylase, which converts vitamin D to its active form, has been found to be coordinated by Nuclear Factor Kappa B (NFkappaB) [5]. All-trans-retinoic-acid (ATRA) was found to significantly reduce nuclear levels of both subunits (p50 and p65) of NF-kappaB [6]. HB-EGF dramatically suppressed NF-kappaB activity and IL-8 release and decreased NO production in cells pretreated with HB-EGF. HB-EGF blocked NF-kappaB activation by inhibiting IkappaB kinase activation and IkappaB phosphorylation and degradation, thus interfering with NF-kappaB nuclear translocation, DNA-binding activity, and NF-kappaB-dependent transcriptional activity [7]. In cultured keratinocytes, real-time PCR analyses revealed that HB-EGF mRNA expression was elevated dose-dependently with atRA, peaking at 12 h. All-trans retinal and all-trans retinol were found to upregulate HB-EGF when used at 0,1-1,0 microM/l to a similiar extent of all-trans retinoic acid at 1,0-10,0 microM [8]. Cubilin is a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand [13]. In rats, cubilin is a 460-kDa multipurpose, multidomain receptor that contains an NH(2)-terminal 110-residue segment followed by 8 epidermal growth factor (EGF)-like repeats and a contiguous stretch (representing nearly 88% of its mass) [11]. This indicates that a significant upregulation of Heparin binding-EGF may strongly affect cubulin receptors, thus being one pathway of (Ro)accutane inhibition of endocytosis in exposed human subjects. This is further confirmed by the finding that heparin inhibits binding of thyroglobulin to the endocytotic receptor megalin [12] , which also, in a similiar manner binds the plasma carrier for vitamin D, vitamin D binding protein [13].
Inhibition of kidney function of vitamin D-metabolism and endocytosis
In endocytic receptor megalin deficient mice, it has been shown that the 1alpha-hydroxylase can also be coregulated by megalin, and a fall in kidney vitamin D metabolites seems to be accompanied by a raise in TGF-beta1 target genes [9]. Megalin is highly expressed in the proximal tubules of the kidney. This receptor is essential for the renal uptake and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3 [10, 17 and more].
Receptor expression and function
The Vitamin D Receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1alpha,25-dihydroxyvitamin D3 [1]. Receptors bind to hormone response elements (HREs) via their DNA-binding domains (DBDs) [2]. In small doses RARs/RXRs physically interact with Sp1, potentiate Sp1 binding to the GC box motifs [15]. The nucleotide sequence of the Sp1 region is well conserved between the mouse, the human, and the chicken VDR genes, suggesting an important role for these Sp1 sites. Gel shift analysis of the four Sp1 sites of the mVDR promoter has confirmed specific binding complexes to Sp1-1, Sp1-2, and Sp1-4 (Sp1-3 rather binds an unknown complex that is unable to bind the canonical Sp1 GGGGCGGGGC). Deletion or mutation of all the Sp1 sites eliminates promoter activity [16]. It is here suggested that a high dose RA as opposed to a small dose, inhibits Sp1 formation and binding.
The Vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by three base pairs of spacer DNA. Binding of 1alpha,25-dihydroxyvitamin D(3) to the full-length VDR causes destabilization of the VDR homodimer and formation of a heterodimeric complex with the 9-cis retinoic acid receptor (RXR) [2].
Traditional targets for 1alpha,25-dihydroxyvitamin D3 action include tissues involved in the maintenance of calcium homeostasis, bone development and remodeling including the bone, kidney, skeletal and cardiac muscle. PGC-1alpha, a transcriptional coactivator which plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in the kidney, heart, liver and skeletal muscle tissues [1]. The VDR also plays a role in cellular proliferation and differentiation [2]. The 1,25-dihydroxyvitamin D3 receptor (VDR), is also expressed in the human brain, where its function is not clarified, as well as 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents [4]. Down-regulation of 1alpha-hydroxylase promoter through NFkappaB signaling may contribute to the pathogenesis of inflammation-associated osteopenia/osteoporosis [5].
1,25-dihydroxyvitamin D3 (D3) is found accelerate integrin beta 3 transcription [14], signifying that a clinical 1,25-dihydoxyvitamin D3 deficiency likely decreases integrin beta 3 transcription, this due to that the integrin beta 3 is suggested to contain a VDRE.
For further information about VDR receptor expression:
Genecards - VDR
(Genecards database)
GenAtlas - VDR
(GenAtlas database)
For further information about megalin/gp330/LRP-2
Genecards - LRP-2
(Genecards database)
