Post by Max on Jun 30, 2005 7:14:44 GMT -5
Significant inhibition of thyroid receptors
Retinoic acid is involved in important physiological processes such as the regulation of growth and differentiation of several tissues, including the pituitary gland. These biological effects are mediated by their binding to two specific intracellular receptors termed retinoic acid and retinoid X receptors, RARs, RXR, respectively). AlphaRXR mRNA expression was demonstrated using the reverse transcription coupled to polymerase chain reaction (RT-PCR) in the human pituitary gland suggesting the possibility that RXR may regulate the human pituitary gene expression and hormone secretion [7]. In human nontumorous pituitaries. RXR alpha was expressed in the nuclei of almost all cells, while RXR gamma was only expressed in thyrotropin (TSH) cells and in some cells positive for growth hormone (GH) and glycoprotein alpha-subunit (alpha SU) [8].
In rat GH1 cells, a cell type located in the pituitary gland, a 50-70 % inhibition of thyroid receptors was found, exposed to doses that are comparable to those seen in (Ro)accutane exposure in acne-subjects [2].
Significant inhibition of growth hormone-releasing hormone receptor (GHRH-R) internalization and expression and downregulation of growth hormone secretagogue receptor (GHS-R)
In small doses retinoic acid is found to stimulate GH-secretion. In rat pituitary GH3 cells, hydrocortisone is also known to stimulate GH secretion. 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. Retinoic acid selectively stimulates basal and HCT-induced GH secretion and mRNA levels in these cells in a dose- and time-dependent manner [1]. However, in massive doses, as seen in (Ro)accutane exposed human subjects, evidence is pointing out that an opposite effect is present, a significant inhibition of GH secretion.
The neuropeptide growth hormone-releasing hormone (GHRH) exerts a crucial role in the anterior pituitary to stimulate growth hormone secretion and synthesis. GHRH is also involved in somatotroph proliferation and differentiation. These biological responses are initiated by the high affinity binding of GHRH to a G-protein-coupled receptor (GPCR). Activation of the pituitary GHRH receptor (GHRH-R) exclusively localized on somatotroph cells, predominantly induces the production of cAMP and Ca2+ influx [3]. Hoffman la Roche itself has admitted to a significantly increased alkaline phosphatase in human subjects exposed to (Ro)accutane [0]. In rat brain cell membranes, AP-2 á subunits are redistributed to the cytosol by exposure to alkaline phosphatase due to dephosphorylation of these proteins [4]. In rats, hGHRH-R internalization is suggested to be AP-2-clathrin-dependent, while fatty acid acylation of rGHRH-R appears to be a prerequisite to caveolin-dependent internalization. Both receptor primary structure and concentration at the plasma membrane play important roles in internalization and trafficking of specific G-protein-coupled receptors (GPCR) [3]. It is here suggested that the (Ro)accutane induced translocation of AP-2 subunits, inhibits the clathrin dependent internalization process of the growth hormone releasing receptor, thus leading to an inhibited release of growth hormone, and inhibition of somatroph proliferation and differentiation.
In human acne-subjects exposed to (Ro)accutane, levels of thyroxine and triiodothyronine were significantly lower after exposure (p less than 0.05), indicating a (Ro)accutane induced clinical thyroid deficiency (hypothyroidism) [5]. In adult rats, thyroid hormones regulate growth hormone (GH) secretion by actions both at the hypothalamus and at the pituitary gland. At the level of the pituitary, thyroid hormones increase GH and GH-releasing hormone receptor (GHRH-R) mRNA expression. T3 increased pituitary GHS-R mRNA levels in a dose- and time-dependent manner [6]. It is suggested that a (Ro)accutane exposure in human subjects also downregulates both GHRH-R and GHS-R as additional effects in its inhibition of growth hormone secretion.
Retinoic acid is involved in important physiological processes such as the regulation of growth and differentiation of several tissues, including the pituitary gland. These biological effects are mediated by their binding to two specific intracellular receptors termed retinoic acid and retinoid X receptors, RARs, RXR, respectively). AlphaRXR mRNA expression was demonstrated using the reverse transcription coupled to polymerase chain reaction (RT-PCR) in the human pituitary gland suggesting the possibility that RXR may regulate the human pituitary gene expression and hormone secretion [7]. In human nontumorous pituitaries. RXR alpha was expressed in the nuclei of almost all cells, while RXR gamma was only expressed in thyrotropin (TSH) cells and in some cells positive for growth hormone (GH) and glycoprotein alpha-subunit (alpha SU) [8].
In rat GH1 cells, a cell type located in the pituitary gland, a 50-70 % inhibition of thyroid receptors was found, exposed to doses that are comparable to those seen in (Ro)accutane exposure in acne-subjects [2].
Significant inhibition of growth hormone-releasing hormone receptor (GHRH-R) internalization and expression and downregulation of growth hormone secretagogue receptor (GHS-R)
In small doses retinoic acid is found to stimulate GH-secretion. In rat pituitary GH3 cells, hydrocortisone is also known to stimulate GH secretion. 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. Retinoic acid selectively stimulates basal and HCT-induced GH secretion and mRNA levels in these cells in a dose- and time-dependent manner [1]. However, in massive doses, as seen in (Ro)accutane exposed human subjects, evidence is pointing out that an opposite effect is present, a significant inhibition of GH secretion.
The neuropeptide growth hormone-releasing hormone (GHRH) exerts a crucial role in the anterior pituitary to stimulate growth hormone secretion and synthesis. GHRH is also involved in somatotroph proliferation and differentiation. These biological responses are initiated by the high affinity binding of GHRH to a G-protein-coupled receptor (GPCR). Activation of the pituitary GHRH receptor (GHRH-R) exclusively localized on somatotroph cells, predominantly induces the production of cAMP and Ca2+ influx [3]. Hoffman la Roche itself has admitted to a significantly increased alkaline phosphatase in human subjects exposed to (Ro)accutane [0]. In rat brain cell membranes, AP-2 á subunits are redistributed to the cytosol by exposure to alkaline phosphatase due to dephosphorylation of these proteins [4]. In rats, hGHRH-R internalization is suggested to be AP-2-clathrin-dependent, while fatty acid acylation of rGHRH-R appears to be a prerequisite to caveolin-dependent internalization. Both receptor primary structure and concentration at the plasma membrane play important roles in internalization and trafficking of specific G-protein-coupled receptors (GPCR) [3]. It is here suggested that the (Ro)accutane induced translocation of AP-2 subunits, inhibits the clathrin dependent internalization process of the growth hormone releasing receptor, thus leading to an inhibited release of growth hormone, and inhibition of somatroph proliferation and differentiation.
In human acne-subjects exposed to (Ro)accutane, levels of thyroxine and triiodothyronine were significantly lower after exposure (p less than 0.05), indicating a (Ro)accutane induced clinical thyroid deficiency (hypothyroidism) [5]. In adult rats, thyroid hormones regulate growth hormone (GH) secretion by actions both at the hypothalamus and at the pituitary gland. At the level of the pituitary, thyroid hormones increase GH and GH-releasing hormone receptor (GHRH-R) mRNA expression. T3 increased pituitary GHS-R mRNA levels in a dose- and time-dependent manner [6]. It is suggested that a (Ro)accutane exposure in human subjects also downregulates both GHRH-R and GHS-R as additional effects in its inhibition of growth hormone secretion.
