Post by Max on Jun 12, 2005 18:58:12 GMT -5
The superfamily of nuclear hormone receptors (NHRs)
The thyroid receptors (TRs) and retinoid receptors (RXRs, RARs) belong to the large superfamily of nuclear hormone receptors (NHRs) that regulate gene transcription. These proteins control a diverse set of target genes in response to specific physiological signals. Family members include the endocrine receptors, such as the estrogen (ER) and androgen (AR) receptors; the adopted orphan receptors, such as the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR); and the orphan receptors, receptors that do not require an endogenous ligand or for which a ligand has yet to be identified, such as steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1) [1]. The receptor family also includes receptors for progesterone (PR) glucocorticoids (GR) and mineralocorticoids (MR) [8].
Each receptor forms hetero/homo-dimers with the compounds that they are sensitive to, and binds to DNA nuclear response elements. These can be described as hormone or steroid response elements (HREs or SREs). The HREs can then be subdivided into smaller sequences [8]. The response elements inserts transcription through either binding directly to the DNA or acting as a cofactor [9].
Smaller sequences of HREs include TREs and AREs. In the case of the thyroid receptor, it binds to mainly to thyroid response elements (TREs) [9], in the case of androgen receptor (AR) it binds to mainly to androgen response elements (AREs) [8].
Significant androgen receptor inhibition and inhibition of 5-alpha-r
The 5-alpha-reductase (5-alpha-r), an enzyme known to convert testosterone to the more potent and active compound dihydrotestosterone (DHT), was found to be inhibited by 50% in human prostate cells exposed to (Ro)accutane in doses comparable to associated plasma concentrations in (Ro)accutane exposed subjects with acne [2]. The 5-alpha-r has been found to be significantly inhibited by (Ro)accutane in acne-subjects in several repeated studies [5, [url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1827343&query_hl=52
] 6, [/url] 7 and more]. The androgen receptor (AR) gene promoter does not contain the TATA or CAAT box, but it contains a long (approximately 90-bp) homopurine/homopyrimidine (pur/ pyr) stretch immediately upstream of the Sp1-binding GC box site. This pur-pyr stretch is conserved at the same proximal position in the rat, mouse, and human AR gene promoters. TATA-less AR gene promoter, multiple weak Sp1 sites at the pur/pyr region adjacent to the GC box can provide a readily available source of this transcription factor to the functional GC box, thereby facilitating the assembly of the initiation complex [13].
It is here suggested that a similiar 50% suppression of the 5-alpha-r through suppression of androgen receptors occurs after (Ro)accutane exposure in all human cells carrying retinoid receptors, including related cells found in various parts of the brain.
The 5-alpha reductase is genetic and dependant on androgen receptor polymorphism [3]. Androgen receptors (AR) as well as thyroid receptors (TR) belong to the superfamily of nuclear hormone receptors where also the retinoid receptors belong [1]. The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone [8].
Significant thyroid receptor inhibition
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 [4]. It is here suggested that all cell lines carrying retinoid and thyroid receptors in humans are suppressed in a similiar manner.
Since a 50 % inhibition of the 5-alpha reductase is found in human cells in related doses to those seen in (Ro)accutane exposure of acne-subjects, and a 50-70% inhibition of thyroid receptors belonging to the same receptor complex, such as TRbeta2 is observed in related doses to those seen in (Ro)accutane exposure in acne-patients, it is here suggested that a general 50% inhibition of the androgen (AR) and thyroid (TR) receptors occurs in various parts of the body and brain, in subjects exposed to (Ro)accutane in doses associated with what is received in acne-subjects.
Subdividing the hormonal response elements further, C´delta2 is a fragment suggested to be of importance for androgen function in the HREs. In mice C'delta2 expression was found not to be driven by glucocorticoids, as adrenalectomy had little effect, but are suggested to be dependent on the NF-kappaB-like element absent from the C'delta9 fragment [10]. The same conclusion was drawn in another study, NF-kappa B bound the region of C' delta 2 absent from C' delta 9. Expression of I kappa B decreased response of C' delta 2, but not C' delta 9, confirming a permissive role of NF-kappa B in steroid activation [11]. A nearly identical effect is suggested in humans.
Transcription factor AP-1 has been found to be modulated by thyroid receptors and TREs [12].
To further confirm the drastic anti-androgen and hypothyroid response in subjects exposed to (Ro)accutane, both AP-1, AP-2 and NFkappaB was found to be significantly altered in subjects exposed to retinoic acid in repeated studies.
The thyroid receptors (TRs) and retinoid receptors (RXRs, RARs) belong to the large superfamily of nuclear hormone receptors (NHRs) that regulate gene transcription. These proteins control a diverse set of target genes in response to specific physiological signals. Family members include the endocrine receptors, such as the estrogen (ER) and androgen (AR) receptors; the adopted orphan receptors, such as the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR); and the orphan receptors, receptors that do not require an endogenous ligand or for which a ligand has yet to be identified, such as steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1) [1]. The receptor family also includes receptors for progesterone (PR) glucocorticoids (GR) and mineralocorticoids (MR) [8].
Each receptor forms hetero/homo-dimers with the compounds that they are sensitive to, and binds to DNA nuclear response elements. These can be described as hormone or steroid response elements (HREs or SREs). The HREs can then be subdivided into smaller sequences [8]. The response elements inserts transcription through either binding directly to the DNA or acting as a cofactor [9].
Smaller sequences of HREs include TREs and AREs. In the case of the thyroid receptor, it binds to mainly to thyroid response elements (TREs) [9], in the case of androgen receptor (AR) it binds to mainly to androgen response elements (AREs) [8].
Significant androgen receptor inhibition and inhibition of 5-alpha-r
The 5-alpha-reductase (5-alpha-r), an enzyme known to convert testosterone to the more potent and active compound dihydrotestosterone (DHT), was found to be inhibited by 50% in human prostate cells exposed to (Ro)accutane in doses comparable to associated plasma concentrations in (Ro)accutane exposed subjects with acne [2]. The 5-alpha-r has been found to be significantly inhibited by (Ro)accutane in acne-subjects in several repeated studies [5, [url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1827343&query_hl=52
] 6, [/url] 7 and more]. The androgen receptor (AR) gene promoter does not contain the TATA or CAAT box, but it contains a long (approximately 90-bp) homopurine/homopyrimidine (pur/ pyr) stretch immediately upstream of the Sp1-binding GC box site. This pur-pyr stretch is conserved at the same proximal position in the rat, mouse, and human AR gene promoters. TATA-less AR gene promoter, multiple weak Sp1 sites at the pur/pyr region adjacent to the GC box can provide a readily available source of this transcription factor to the functional GC box, thereby facilitating the assembly of the initiation complex [13].
It is here suggested that a similiar 50% suppression of the 5-alpha-r through suppression of androgen receptors occurs after (Ro)accutane exposure in all human cells carrying retinoid receptors, including related cells found in various parts of the brain.
The 5-alpha reductase is genetic and dependant on androgen receptor polymorphism [3]. Androgen receptors (AR) as well as thyroid receptors (TR) belong to the superfamily of nuclear hormone receptors where also the retinoid receptors belong [1]. The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone [8].
Significant thyroid receptor inhibition
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 [4]. It is here suggested that all cell lines carrying retinoid and thyroid receptors in humans are suppressed in a similiar manner.
Since a 50 % inhibition of the 5-alpha reductase is found in human cells in related doses to those seen in (Ro)accutane exposure of acne-subjects, and a 50-70% inhibition of thyroid receptors belonging to the same receptor complex, such as TRbeta2 is observed in related doses to those seen in (Ro)accutane exposure in acne-patients, it is here suggested that a general 50% inhibition of the androgen (AR) and thyroid (TR) receptors occurs in various parts of the body and brain, in subjects exposed to (Ro)accutane in doses associated with what is received in acne-subjects.
Subdividing the hormonal response elements further, C´delta2 is a fragment suggested to be of importance for androgen function in the HREs. In mice C'delta2 expression was found not to be driven by glucocorticoids, as adrenalectomy had little effect, but are suggested to be dependent on the NF-kappaB-like element absent from the C'delta9 fragment [10]. The same conclusion was drawn in another study, NF-kappa B bound the region of C' delta 2 absent from C' delta 9. Expression of I kappa B decreased response of C' delta 2, but not C' delta 9, confirming a permissive role of NF-kappa B in steroid activation [11]. A nearly identical effect is suggested in humans.
Transcription factor AP-1 has been found to be modulated by thyroid receptors and TREs [12].
To further confirm the drastic anti-androgen and hypothyroid response in subjects exposed to (Ro)accutane, both AP-1, AP-2 and NFkappaB was found to be significantly altered in subjects exposed to retinoic acid in repeated studies.
