Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11beta-HSD-1) may function as an 11beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11beta-HSD-1 -/- mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.
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PMID:11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. 940 15

The ACTH test has been used to confirm the diagnosis of adrenal insufficiency and the classic and the non-classic adrenal hyperplasia due to the 3-HSD, 21 OH e 110H deficiencies. This article reviews the historical aspects of the use of ACTH in the diagnosis of hirsutism and points out its mains indications. In spite of new biological molecular advances in the diagnosis of adrenal enzymatic deficiencies, the use of the ACTH test can help the physician to predict both genothipus and fenothipus in populations with hyperandrogenic manifestations due to non-classical or late-onset congenital adrenal hyperplasia.
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PMID:The ACTH test in the diagnosis of hirsutism. 946 Mar 1

The physiological importance of adrenal 21-hydroxylase cytochrome P450 (CYP21) expression is clearly demonstrated by 21-hydroxylase deficiency, which results in adrenal hyperplasia and over-production of C19 steroids, leading to virilization. The mechanisms regulating normal expression of this key enzyme in human adrenocortical cells are ill defined. Herein we examine the role of the calcium, protein kinase C, and protein kinase A signaling pathways in the expression of CYP21 messenger ribonucleic acid (mRNA) using the H295R human adrenocortical cell model. Forskolin (10 mumol/L) treatment caused a progressive increase in CYP21 mRNA levels (maximum, 4-fold; P < 0.05) over 36 h of treatment, whereas angiotensin II (AII; 10 nmol/L) produced a smaller, biphasic rise (maximum, 1.8-fold at 12 h; P < 0.05). K+ (14 mmol/L) also induced a time-dependent (maximal, 1.5-fold at 12 h; P < 0.05) and dose-dependent (P < 0.05 12 mmol/L or above at 20 h) rise in CYP21 mRNA levels. The action of forskolin was reproduced by dibutyryl cAMP, confirming the involvement of cAMP in this response. The action of AII was greater than that of K+ or the calcium channel agonist BAYK8644, suggesting that AII action was not solely through the Ca2+ signaling pathway. The action of AII was reproduced and indeed exceeded by the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA; 10 nmol/L; 5.5-fold increase; P < 0.05). The actions of forskolin alone were not significantly increased by combined treatment with AII, suggesting neither synergy nor attenuation of the effects of protein kinase A activation. This was further demonstrated at the level of mRNA and 21-hydroxylase activity by the observation that the effect of forskolin and TPA in combination did not exceed that of TPA alone. Inhibition of protein synthesis with cycloheximide blocked induction of CYP21 as well as type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSDII) mRNA expression in response to AII, forskolin, and dibutyryl cAMP, but had no effect on 17 alpha-hydroxylase cytochrome P450 (CYP17) or cholesterol side-chain cleavage cytochrome P450 (CYP11A) mRNA. Together, these findings were remarkably similar to those of our previous studies regarding mechanisms regulating 3 beta HSDII expression and underline the existence of a subset of steroidogenic enzymes regulated positively (CYP21 and 3 beta HSDII) as opposed to negatively (CYP17 and CYP11A) by the protein kinase C signaling pathway. The additional finding of a small induction of CYP21 expression in response to increased Ca2+, as previously reported for CYP17, but not 3 beta HSDII, expression, also demonstrates that the mechanisms of control of CYP21 and 3 beta HSDII are not identical. This latter finding may also relate to how CYP21 as well as CYP17 expression continues in the zona reticularis after adrenarche, whereas 3 beta HSD expression declines.
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PMID:Protein kinase A, protein kinase C, and Ca(2+)-regulated expression of 21-hydroxylase cytochrome P450 in H295R human adrenocortical cells. 958 61

Several autosomal recessive disorders affecting the adrenal cortex and its development and leading to defective cortisol biosynthesis are known under the collective term "congenital adrenal hyperplasia" (CAH). Over the last two decades, the genes causing most of these disorders have been identified and molecular genetics may supplement their clinical and biochemical diagnosis. In addition, new treatments have emerged; although gene therapy has yet to be applied in humans, studies are ongoing in gene transfer in adrenocortical cell lines and animal models. In this review, after a brief introduction on the developmental biology and biochemistry of the adrenal cortex and its enzymes, we will list the new developments in the genetics and treatment of diseases causing CAH, starting with the most recent findings. This order happens to follow adrenal steroidogenesis from the mitochondrial entry of cholesterol to cortisol synthesis; it is unlike other presentations of CAH syndromes that start with the most frequently seen syndromes, because the latter were also the first to be investigated at the genetic level and have been extensively reviewed elsewhere. We will start with the latest syndrome to be molecularly investigated, congenital lipoid adrenal hyperplasia (CLAH), which is caused by mutations in the gene coding for the steroidogenic acute regulatory (StAR) protein. We will then present new developments in the genetics of 3-beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 hydroxylase and 17,20-lyase (P450c17), 11 hydroxylase (P450c11 beta), and 21 hydroxylase (P450c21) deficiencies. Alternative treatment approaches and gene therapy experiments are reviewed collectively in the last section, because they are still in their infantile stages.
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PMID:Congenital adrenal hyperplasia: molecular genetics and alternative approaches to treatment. 1048 4

The glucocorticoid metabolising enzymes, 11beta-hydroxysteroid dehydrogenases (11beta-HSD), play a critical role in determining the availability of glucocorticoids to activate their receptors and hence modulate target gene transcription. There are two isozymes, 11beta-HSD-1 and -2, which act in opposing directions. 11beta-HSD-2 acts as a dehydrogenase, converting active corticosterone (cortisol in humans) to its inactive 11-keto derivative (11-dehydrocorticosterone in rodents and cortisone in humans), whereas 11beta-HSD-1 acts as a reductase, regenerating active glucocorticoids in a tissue-specific manner. Owing to the lack of specific inhibitors of these enzymes, it has been difficult to confirm the roles and determine the importance of these enzymes in vivo. Hence, to address this, we produced transgenic mice with null-mutations in the genes encoding the 11beta-HSD-1 or 11beta-HSD-2 enzymes. 11beta-HSD-2 -/- mice show signs of hypertension, hypotonic polyuria, hypokalemia and hypochloremia. These symptoms arise from illicit activation of mineralocorticoid receptors by glucocorticoids, in the absence of the protective action of 11beta-HSD-2. The phenotype is directly comparable to the Syndrome of Apparent Mineralocorticoid Excess, seen in humans with mutations in the 11beta-HSD-2 gene. Mice lacking 11beta-HSD-1, however, show a more subtle phenotype with reduced activation of glucocorticoid-induced processes. They were unable to convert 11-dehydrocorticosterone to corticosterone in vivo, confirming 11beta-HSD-1 as the sole 11-reductase in the mouse. They have elevated circulating levels of plasma corticosterone levels and adrenal hyperplasia, but they also have attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting, and lower glucose levels in response to obesity or stress. Overall, these transgenic models have proved very useful for elucidating the roles of 11beta-HSDs in vivo and will be a unique resource for investigating the importance of each enzyme in the diverse actions of glucocorticoids.
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PMID:Phenotypic analysis of mice bearing targeted deletions of 11beta-hydroxysteroid dehydrogenases 1 and 2 genes. 1116 6

The management of disorders of sexual differentiation (DSD) involves a multidisciplinary approach. The main aim of analysis was to study the phenotype-karyotype correlation in North Indian children with DSD. The records of pediatric DSD were retrieved and characteristics noted. Of total of 58 children, 43 (74.1%) and 10 (17.2%) were raised as males and females respectively. The mean age at presentation was 31.3+/-9 months. The karyotype was 46XY in 45 (77.6%) and 46XX in 12 (20.7%). CAH was commonest cause of DSD (36.2%), followed by gonadal dysgenesis. Of the 15 patients of 46 XY CAH, there were 5 with 17-alpha hydroxylase deficiency, 2 with 3-beta HSD deficiency and one case of lipoid adrenal hyperplasia. There was an excess of genetic males, possibly due to prevalent socio-cultural factors and gender bias favoring males. There is a need to improve the diagnostic facilities and incorporate a team approach in management of DSD.
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PMID:Pediatric disorders of sex development. 1990 13