Post by Max on Jun 12, 2005 18:59:06 GMT -5
Significant interaction with the GH-IGF-axis
In humans, vitamin A and retinoic acid are substances extensively known to be involved in the release of growth hormone [11 and more]. A clear correlation between nocturnal growth hormone (GH) secretion and Vitamin A status was was found in short slowly growing children [12]. However, except for the clear relation between growth hormone and growth, in adults growth hormone is known to mediate a wide variety of metabolic functions. Too low levels of growth hormone in adults results in adult growth hormone deficiency.
Data indicates that (Ro)accutane interacts with the GH/IGF-1 axis through several pathways, and among other things highly likely result in:
x a significant endocrine alteration of circulating GH/IGF-1 through decreased pituitary GH production and release, kidney function and liver function
x decreased receptor function/expression of several to the GH/IGF axis related receptors (partial GH resistance and IGF resistance)
x alteration of IGF binding protein function through alterations in retinoid receptor function and alterations of GC-box binding motifs
An extensive amount of data shows clear interaction between retinoids and the GH/IGF-1 axis. Unfortunately no publicly available study of human acne-subjects exposed to (Ro)accutane clarifies and summarizes well the clinical effects on the GH/IGF-axis.
Vitamin A-deficiency, growth hormone secretion and the GH-gene
In human pituitary cells, Vitamin A and retinoic acid is found to stimulate cAMP release and growth hormone secretion [11]. A nearly identical correlation has been found in rats. In rat pituitary GH3 cells, Retinoic acid <1 microM stimulated growth hormone secretion by 220%. 50 nM HCT stimulated GH secretion 3,5 times and in synergy GH secretion was stimulated seven times [7]. The RXR-specific ligand induced rat growth hormone mRNA in GH3 pituitary cells, indicating that the effects of RA on growth hormone gene expression at least in part involve ligand binding to endogenous RXRs in vivo [13].
Renal failure and alterations of the GH/IGF-1 axis
Inhibition of megalin receptors may induce failure in the circulation of IGF-1, and instead increased urinary levels. In (cy/+) mice, the expression of proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in (cy/+) animals [8].
Found significant interaction between Insulin like growth factor binding protein 3 (IGFBP-3) and RXR-alpha - suggested further significant interaction IGFBP-1 and 3 with retinoids through alterations of binding affinity to GX-box motifs and Sp1 transcription
IGFBP-3 is particulary widely expressed during puberty [Genecards database]. An interaction between nuclear IGFBP-3 and 9-cis retinoic acid receptor-alpha (RXRalpha) exists. Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been shown to be a growth inhibitory, apoptosis-inducing molecule by virtue of its ability to bind IGFs [2].
Human genomic clones encompassing the tissue specific expressed gene IBP-1/IGFBP-1, an insulin-like growth factor binding protein were isolated and characterized. The gene is organized in four exons and spans 5.9 kb. S1 nuclease analysis determined a single transcription start site. The first exon and 5' flanking region are highly GC rich and located in a CpG island. The CpG island enclose the CAAT box, the TATA box, the transcription start site and a potential SP1 transcription factor binding site. The presumptive promoter region is characteristic for genes expressed in a tissue specific fashion. All signals required for cleavage/polyadenylation are located within exon IV, predicting a mRNA of 1.5 kb which is consistent with the size seen on RNA blots [17].
Significantly decreased receptor expression of Insulin receptor substrate 1 (IRS-1) induced by massive doses of retinoic acid
Insulin receptor substrate-1 (IRS-1) mediates signaling from the insulin-like growth factor type-I receptor. All-trans retinoic acid (RA) is found to decrease IRS-1 protein levels in certain breast cancer cells, which are growth arrested by RA [9]. It is here suggested that more cell lines than certain breast cancer cells decrease IRS-1 protein levels and therefore constitute one pathway for inhibition of IGF-1 signaling. IRS-1, an intracellular substrate of the insulin receptor tyrosine kinase, also is heavily phosphorylated on serine and threonine residues; several serine phosphorylation sites alter the function of IRS-1 [10].
In Mv1Lu cells, insulin partially reverses transforming growth factor-beta1 (TGF-beta1) growth inhibition in the presence of alpha5beta1 integrin antagonists. TGF-beta1 appears to induce phosphorylation of IRS-2 in these cells; this is inhibited by a TGF-beta antagonist known to reverse TGF-beta growth inhibition. Stable transfection of 32D myeloid cells (which lack endogenous IRS proteins and are insensitive to growth inhibition by TGF-beta1) with IRS-1 or IRS-2 cDNA confers sensitivity to growth inhibition by TGF-beta1; this IRS-mediated growth inhibition can be partially reversed by insulin in 32D cells stably expressing IRS-2 and the insulin receptor (IR). These results suggest that growth inhibition by TGF-beta1 involves IRS proteins [1].
Interaction with GH-secretion also through hydrocortisone (HCT) receptor modulation
The retinoic acid receptor cDNA bears a 15% homology to the hydrocortisone (HCT) receptor, which thus here is suggested to be one additive pathway of (Ro)accutane induced significant interference with the GH/IGF-axis. In rat pituitary GH3 cells, hydrocortisone is known to stimulate GH secretion. Retinoic acid selectively stimulates basal and HCT-induced GH secretion and mRNA levels in these cells in a dose- and time-dependent manner [7].
In humans, vitamin A and retinoic acid are substances extensively known to be involved in the release of growth hormone [11 and more]. A clear correlation between nocturnal growth hormone (GH) secretion and Vitamin A status was was found in short slowly growing children [12]. However, except for the clear relation between growth hormone and growth, in adults growth hormone is known to mediate a wide variety of metabolic functions. Too low levels of growth hormone in adults results in adult growth hormone deficiency.
Data indicates that (Ro)accutane interacts with the GH/IGF-1 axis through several pathways, and among other things highly likely result in:
x a significant endocrine alteration of circulating GH/IGF-1 through decreased pituitary GH production and release, kidney function and liver function
x decreased receptor function/expression of several to the GH/IGF axis related receptors (partial GH resistance and IGF resistance)
x alteration of IGF binding protein function through alterations in retinoid receptor function and alterations of GC-box binding motifs
An extensive amount of data shows clear interaction between retinoids and the GH/IGF-1 axis. Unfortunately no publicly available study of human acne-subjects exposed to (Ro)accutane clarifies and summarizes well the clinical effects on the GH/IGF-axis.
Vitamin A-deficiency, growth hormone secretion and the GH-gene
In human pituitary cells, Vitamin A and retinoic acid is found to stimulate cAMP release and growth hormone secretion [11]. A nearly identical correlation has been found in rats. In rat pituitary GH3 cells, Retinoic acid <1 microM stimulated growth hormone secretion by 220%. 50 nM HCT stimulated GH secretion 3,5 times and in synergy GH secretion was stimulated seven times [7]. The RXR-specific ligand induced rat growth hormone mRNA in GH3 pituitary cells, indicating that the effects of RA on growth hormone gene expression at least in part involve ligand binding to endogenous RXRs in vivo [13].
Renal failure and alterations of the GH/IGF-1 axis
Inhibition of megalin receptors may induce failure in the circulation of IGF-1, and instead increased urinary levels. In (cy/+) mice, the expression of proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in (cy/+) animals [8].
Found significant interaction between Insulin like growth factor binding protein 3 (IGFBP-3) and RXR-alpha - suggested further significant interaction IGFBP-1 and 3 with retinoids through alterations of binding affinity to GX-box motifs and Sp1 transcription
IGFBP-3 is particulary widely expressed during puberty [Genecards database]. An interaction between nuclear IGFBP-3 and 9-cis retinoic acid receptor-alpha (RXRalpha) exists. Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been shown to be a growth inhibitory, apoptosis-inducing molecule by virtue of its ability to bind IGFs [2].
Human genomic clones encompassing the tissue specific expressed gene IBP-1/IGFBP-1, an insulin-like growth factor binding protein were isolated and characterized. The gene is organized in four exons and spans 5.9 kb. S1 nuclease analysis determined a single transcription start site. The first exon and 5' flanking region are highly GC rich and located in a CpG island. The CpG island enclose the CAAT box, the TATA box, the transcription start site and a potential SP1 transcription factor binding site. The presumptive promoter region is characteristic for genes expressed in a tissue specific fashion. All signals required for cleavage/polyadenylation are located within exon IV, predicting a mRNA of 1.5 kb which is consistent with the size seen on RNA blots [17].
Significantly decreased receptor expression of Insulin receptor substrate 1 (IRS-1) induced by massive doses of retinoic acid
Insulin receptor substrate-1 (IRS-1) mediates signaling from the insulin-like growth factor type-I receptor. All-trans retinoic acid (RA) is found to decrease IRS-1 protein levels in certain breast cancer cells, which are growth arrested by RA [9]. It is here suggested that more cell lines than certain breast cancer cells decrease IRS-1 protein levels and therefore constitute one pathway for inhibition of IGF-1 signaling. IRS-1, an intracellular substrate of the insulin receptor tyrosine kinase, also is heavily phosphorylated on serine and threonine residues; several serine phosphorylation sites alter the function of IRS-1 [10].
In Mv1Lu cells, insulin partially reverses transforming growth factor-beta1 (TGF-beta1) growth inhibition in the presence of alpha5beta1 integrin antagonists. TGF-beta1 appears to induce phosphorylation of IRS-2 in these cells; this is inhibited by a TGF-beta antagonist known to reverse TGF-beta growth inhibition. Stable transfection of 32D myeloid cells (which lack endogenous IRS proteins and are insensitive to growth inhibition by TGF-beta1) with IRS-1 or IRS-2 cDNA confers sensitivity to growth inhibition by TGF-beta1; this IRS-mediated growth inhibition can be partially reversed by insulin in 32D cells stably expressing IRS-2 and the insulin receptor (IR). These results suggest that growth inhibition by TGF-beta1 involves IRS proteins [1].
Interaction with GH-secretion also through hydrocortisone (HCT) receptor modulation
The retinoic acid receptor cDNA bears a 15% homology to the hydrocortisone (HCT) receptor, which thus here is suggested to be one additive pathway of (Ro)accutane induced significant interference with the GH/IGF-axis. In rat pituitary GH3 cells, hydrocortisone is known to stimulate GH secretion. Retinoic acid selectively stimulates basal and HCT-induced GH secretion and mRNA levels in these cells in a dose- and time-dependent manner [7].
