Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) catalyzes the conversion of physiological glucocorticoids to inactive products, thus protecting nonselective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone selectivity in vivo) and modulating glucocorticoid access to mineralocorticoid receptors and glucocorticoid receptors in other tissues. Detection of multiple mRNA and immunoreactive 11 beta-OHSD species in kidney, but not liver, extracts suggests the presence of tissue-specific isoforms. To determine whether differential promoter usage might explain the mRNA heterogeneity we cloned and sequenced rat 11 beta-OHSD genomic DNA. Total identity was found between the nucleotide sequence of exons 1 and 2 and the previously published rat liver cDNA. Using both primer extension and RNase protection analyses we found the predominant transcription start site in liver (+1) is 105 base pairs (bp)5' of the start of translation. In kidney two additional Cap sites were detected: 1) 264 bp 5' of exon 1; there is no in-phase open reading frame, suggesting the additional 5' sequence is not translated; and 2) 65 bp upstream of exon 2, within intron A; the predicted truncated protein lacks the first 26 hydrophobic residues. Oligonucleotide probes specific to transcripts arising from each promoter confirmed that all three are employed in kidney, whereas a single predominant species was found in liver, thus demonstrating tissue-specific differential promoter usage of the 11 beta-OHSD gene.
Mol Endocrinol 1992 Jul
PMID:Differential promoter usage by the rat 11 beta-hydroxysteroid dehydrogenase gene. 150 21

Streptomyces hydrogenans 3 alpha,20 beta-hydroxysteroid dehydrogenase reduces the C20 ketone on glucocorticoids and progestins. We find that two licorice-derived compounds, glycyrrhizic acid and carbenoxolone, inhibit this enzyme with microM Kis. Inhibition is competitive, indicating that these compounds are binding at or close to the catalytic site. Carbenoxolone's high aqueous solubility and affinity for 3 alpha,20 beta-hydroxysteroid dehydrogenase enabled us to prepare crystals of a carbenoxolone-NADH-enzyme ternary complex, which preliminary X-ray analysis indicates has a crystal structure that is significantly different from that of the 3 alpha,20 beta-hydroxysteroid dehydrogenase-NADH complex. A comparison of the tertiary structures of these two complexes should prove useful in understanding this enzyme's catalytic mechanism, as well as those of two homologous enzymes, mammalian 11 beta-hydroxysteroid dehydrogenase and 15-hydroxyprostaglandin dehydrogenase that also are inhibited by carbenoxolone.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Inhibition of Streptomyces hydrogenans 3 alpha,20 beta-hydroxysteroid dehydrogenase by licorice-derived compounds and crystallization of an enzyme-cofactor-inhibitor complex. 152 45

The licorice derivative, carbenoxolone sodium, is a potent inhibitor of the enzyme 11 beta-hydroxysteroid dehydrogenase. When this enzyme is suppressed or is absent, endogenous glucocorticoids induce mineralocorticoid-like sodium retention by the kidney. Carbenoxolone sodium administered in vivo to an adrenalectomized rat has also recently been shown to enhance the mineralocorticoid response to submaximal concentrations of aldosterone, deoxycorticosterone (DOC) and 11-dehydrocorticosterone (compound A). In the present studies conducted on the urinary bladder isolated from the Dominican toad, Bufo marinus, a concentration of carbenoxolone sodium shown previously to increase glucocorticoid-induced sodium transport (2.5 x 10(-5) M) did not appear to alter the response to submaximal concentrations of aldosterone 10(-8) M, DOC 10(-7) M, or compound A 10(-5) M. These findings are consistent with the view that in the whole animal carbenoxolone sodium may modify additional steroid metabolic pathways and/or physiological processes in several organs to produce the enhanced renal response to mineralocorticoids and compound A.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Effect of carbenoxolone sodium on steroid-induced sodium transport in the toad bladder: further studies. 152 50

Three enzymatic activities (3 alpha/beta-hydroxysteroid dehydrogenase, 20 beta- and 20 alpha-hydroxysteroid dehydrogenases) were measured in testes of pigs as a function of age. Earlier studies reported a highly purified 20 beta-hydroxysteroid dehydrogenase from neonatal pig testes that also showed strong 3 alpha/beta-hydroxysteroid dehydrogenase activity [Ohno et al., J. Steroid Biochem. Molec. Biol. 38 (1991) 787-794]. We report here that neonatal pigs testis is rich in 3 alpha/beta- and 20 beta-hydroxysteroid dehydrogenase activities, both of which fall to low levels (measured as specific activity) at 60 days. Thereafter the activity of 3 alpha/beta-reduction rises to high levels whereas 20 beta-reduction remains low. Activity of 20 alpha-reduction is of intermediate level in the neonate, falls to a nadir at 60 days and rises to high levels in the mature animal. Western blots of cytosolic proteins show that the bifunctional enzyme (3 alpha/beta-plus 20 beta-hydroxysteroid dehydrogenase) is high in neonatal testes and falls to low levels at maturity. It is proposed that the neonatal testis possesses the bifunctional enzyme which is replaced by a second enzyme at maturity, that is a 3 alpha/beta-hydroxysteroid dehydrogenase without 20 beta-reductase activity. The possible functional significance of these changes is considered.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Ontogeny of testicular steroid dehydrogenase enzymes in pig (3 alpha/beta-, 20 alpha- and 20 beta-): evidence for two forms of 3 alpha/beta-hydroxysteroid dehydrogenase. 155 17

Various flavonoids, such as genistein, luteolin, and coumestrol, have actions in mammals that are mediated by binding either to classical estrogen receptors or to type II receptors, which also bind estrogen. These actions are of intense interest because they may be the basis for the protective actions of plants against certain cancers, such as breast cancer. The biological activity of flavonoids in mammals raises some questions. Is the hormonal action of flavonoids "an accident" derived from their phenolic groups and general hydrophobicity, which gives them some properties in common with estrogens? Or do flavonoids regulate gene transcription in other organisms? And, if so, is there a connection between their actions in these organisms and in mammals? Some answers to these questions are provided by the actions of plant-derived flavonoids in regulating gene transcription in rhizobia, bacteria that form nitrogen-fixing nodules in the roots of legumes, which has several interesting similarities with steroid-mediated actions in vertebrates. First, there is specificity in the actions of flavonoids in rhizobia; oxidation or reduction of the flavonoid or removal of a hydroxyl group can alter its biological activity. Moreover, some flavonoids are anti-inducers functioning like steroid antagonists to negate the actions of inducers. Also there are sequence similarities between various steroid metabolizing enzymes and proteins found in rhizobia, which indicates that these proteins are derived from a common ancestor. For example, 17 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone a C17 on estrogens and androgens, 11 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C11 of glucocorticoids, and 3 alpha,20 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C20 of corticosteroids, are homologs of proteins found in rhizobia. Thus, the binding of flavonoids to vertebrate proteins may represent an evolutionary linkage between the actions of steroids in mammals and communication between plants and rhizobia.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Evolution of regulation of steroid-mediated intercellular communication in vertebrates: insights from flavonoids, signals that mediate plant-rhizobia symbiosis. 156 8

In vitro studies on both the purified cytosolic mineralocorticoid receptor (MR) and the recombinant expressed human MR have shown that it is non-specific and does not distinguish between cortisol and aldosterone. These contrast with the apparent in vivo selectivity of the MR in tissues such as the kidney for aldosterone in preference to cortisol despite the 100-fold molar excess of cortisol. This review gives the evidence that indicates that 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), the enzyme responsible for the interconversion of cortisol and inactive cortisone, acts as a protective mechanism for the MR. In aldosterone-selective tissues it shuttles cortisol to cortisone and thus prevents glucocorticoid access. Aldosterone itself is not a substrate for the enzyme. The current data suggest that this is an autocrine system with both the enzyme and the MR present within the same cell. In certain tissues such as the kidney there may also be additional upstream steroid metabolism indicating a paracrine system. Lack of this protective system results in cortisol acting as a potent mineralocorticoid. This may be congenital as in the apparent mineralocorticoid excess syndrome or acquired secondary to liquorice-induced inhibition of 11 beta-OHSD. In addition to its role in MR protection 11 beta-OHSD may also be important in modulating steroid access to glucocorticoid receptors. The ontogeny of the enzyme in the testis and the brain suggests that its tissue-specific control may be crucial in allowing normal development.
J Steroid Biochem Mol Biol 1991 Nov
PMID:The cortisol-cortisone shuttle and the apparent specificity of glucocorticoid and mineralocorticoid receptors. 165 46

Oral administration of cortisone acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient 'first pass' hepatic conversion of the biologically inactive cortisone (E) to cortisol (F) by the 11-reductase component of the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) system is required for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. 11-beta-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving cortisone acetate therapy. In this paper, we describe THE and THF concentration in 24 h urine samples collected every 3-6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving cortisone acetate and 9 alpha-fluorohydrocortisone since diagnosis and were investigated for 2-4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5 beta, 17 alpha-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime-trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean +/- SD) was significantly higher in patients during periods of poor control (6.56 +/- 2.51, P less than 0.001) compared with periods of good control (3.73 +/- 0.96) in the same patients. THE/THF levels were also significantly (P less than 0.001) higher in CAH patients, irrespective of the level of control, than those for the normal subjects (1.79 +/- 0.20). Furthermore, THE excretion was significantly higher during periods of poor control compared with good control at all doses of cortisone acetate administered (10-50 mg/day). There were no significant differences in THF excretion. THE levels also rose significantly (P less than 0.001) in response to increasing total dose during periods of poor control. The increase in THF excretion was slight and significant only at doses greater than 40 mg/day compared with doses less than 15 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1991 Oct
PMID:A possible defect in the inter-conversion between cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving cortisone acetate therapy. 191 35

Using specific antisera to purified rat liver 11 beta-hydroxysteroid dehydrogenase (11-HSD), we showed that the antigen is widely distributed in rat organs. Enzyme activity and immunoreactivity generally corresponded. Highest by both criteria were liver, testis, kidney and lung. In some tissues (epididymis, pancreas and duodenum) activity was found, but antigen corresponding to 11-HSD at a Mw of 34 kDa was absent. It is suggested that these tissues have alternate enzyme forms. The 11-HSD of brain and liver were compared. Brain enzyme may control selective binding of aldosterone to Type I receptors in the hippocampus and other regions. Rat brain 11-HSD resembled that of liver or kidney in most characteristics. It differed in (a) its steroid specificity: cortisol was a good substrate for liver 11-HSD, and a poor substrate for brain enzyme; (b) stability of 11-oxoreductase (11-OR) component. Brain 11-OR was not readily inactivated; 11-OR from other tissues lost activity rapidly and spontaneously. The variations in properties of 11-HSD in specific tissues may reflect aspects of its various specific functions.
J Steroid Biochem Mol Biol 1991
PMID:Heterogeneity of 11 beta-hydroxysteroid dehydrogenase in rat tissues. 195 55

Human lung tissue converts hydrocortisone to cortisone by the action of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). Since cortisone is inactive as an antiinflammatory steroid, the action of this enzyme may regulate the local antiinflammatory effects of glucocorticoids in the lung. Minced human lung tissue (100 mg in 500 microliters medium) metabolized approximately 50% of added [3H]hydrocortisone within 2 h in most lung specimens. Metabolism was linear during this period and was found to occur over a broad range of concentrations of hydrocortisone (1 to 1,000 nM). Metabolism of hydrocortisone was not observed in minced pulmonary blood vessels or airways (2 to 3 mm), and pleura (containing some adherent parenchyma) had less activity than parenchyma. Cultured human tracheal epithelial cells metabolized hydrocortisone, while umbilical vein endothelial cells did not. Since glycyrrhizin, glycyrrhetinic acid, and carbenoxolone have antiinflammatory properties and have recently been shown to interfere with steroid metabolism in renal tissues, their effects on 11 beta-HSD in human lung tissue have been tested. Conversion of hydrocortisone to cortisone by lung tissue was inhibited by glycyrrhetinic acid (IC50, approximately 2.5 x 10(-8) M) and carbenoxolone (1.5 x 10(-7) M), but not glycyrrhizin (greater than 10(-5) M). It is proposed that inhibition of the metabolism of hydrocortisone by 11 beta-HSD may partially explain the known antiinflammatory actions of orally administered glycyrrhetinic acid and carbenoxolone and that intrapulmonary administration of these compounds may produce antiinflammatory effects targeted to the lung.
Am J Respir Cell Mol Biol 1991 Feb
PMID:Potential regulation of inflammation in the lung by local metabolism of hydrocortisone. 199 Oct 73

The enzyme 11 beta-hydroxysteroid dehydrogenase, by converting cortisol and corticosterone to their receptor-inactive 11-keto metabolites cortisone and 11-dehydrocorticosterone, appears crucial to the aldosterone-selectivity of renal mineralocorticoid receptors. Levels of enzyme activity in the rat kidney, measured by conversion of cortisol to cortisone, are unaltered by changes in adrenal or thyroid status, or by castration in either sex; in contrast, oestrogen administration increases enzyme activity in male rats.
J Steroid Biochem Mol Biol 1991 Feb
PMID:Renal 11 beta-hydroxysteroid dehydrogenase activity: effects of age, sex and altered hormonal status. 200 48


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