A new defect in the peripheral conversion of cortisone to cortisol

Phillipou, G.; Higgins, Bruce

doi:10.1016/0022-4731(85)90451-0

Cited by 80 publications

(35 citation statements)

References 5 publications

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“…If the lack of 11-DHC reactivation to corticosterone is of importance in overall glucocorticoid production and tissue activation, it might be anticipated that there would be increased drive from the hypothalamic-pituitary-adrenal axis to restore homeostasis. Intriguingly, adrenal hyperplasia has been described in a unique female patient with presumed 11␤-reductase deficiency (41). This contention is further supported in 11␤-HSD-1 null mice, in which adrenal weight is increased, caused, in large part, by increased adrenal cortical size.…”

Section: Discussionsupporting

confidence: 50%

11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress

Kotelevtsev¹,

Holmes²,

Burchell³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

832

670

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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 11␤-hydroxysteroid dehydrogenases (11␤-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11␤-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11␤-HSD-1) may function as an 11␤-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 11␤-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 11␤-HSD-1 ؊͞؊ mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11␤-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.

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Section: Discussionsupporting

confidence: 50%

11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress

Kotelevtsev¹,

Holmes²,

Burchell³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

832

670

View full text Add to dashboard Cite

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“…However, virtually all the urinary metabolites are excreted as 11-oxo-metabolites (THE) with very low/ undetectable levels of THF and allo-THF appearing in the urine. Typical THF+allo-THF:THE ratios of <0·05 (normal adult range 0·7-1·3) have been reported (Phillipou & Higgins 1985). (It is of interest that similar patterns of cortisol metabolism are observed in the normal neonatal period.)…”

Section: Cortisone Reductase Deficiencymentioning

confidence: 92%

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Draper¹,

Stewart²

2005

Journal of Endocrinology

346

294

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“…One could also speculate that the discrepant activity/mRNA data reflects the presence of another 11 -HSD isozyme, an isozyme which acts in vivo as a pure reductase. In keeping with this suggestion, several patients have been described with a 'polycystic ovary syndrome'-like phenotype, who show a defect in the conversion of cortisone to cortisol (Phillipou & Higgins 1985) but who do not have a mutation in the 11 -HSD1 gene (Nikkila et al 1993).…”

Section: Regulation Of 11 -Hsd In Hepatocytes · M L Ricketts and Othementioning

confidence: 96%

Regulation of 11 beta-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes

Ricketts

Shoesmith²,

Hewison³

et al. 1998

Journal of Endocrinology

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Two isozymes of the enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD) are responsible for the interconversion of the active glucocorticoid, cortisol in man, (corticosterone in the rodent), to the inactive 11-keto metabolite, cortisone (11-dehydrocorticosterone). We have examined the regulation of type 1 11 -HSD (11 -HSD1) using primary cultures of rat and human hepatocytes, both of which express only 11 -HSD1. Only 11 oxo-reductase activity could be demonstrated in cultured hepatocytes (apparent K m for cortisone 382 43 nM in human hepatocytes, apparent K m for 11-dehydrocorticosterone 14·6 1·5 µM in rat hepatocytes). There exists a marked discrepancy between 11 -HSD oxo-reductase activity and 11 -HSD1 mRNA levels in cultured human hepatocytes and human liver. Thus oxo-reductase specific activity is much higher in the cultured hepatocytes (7·2 0·01 nmoles cortisol/mg/h vs 0·89 0·06 for whole liver homogenates) whilst the converse is true for steady state 11 -HSD1 mRNA levels (0·78 0·02 vs 1·94 0·07 in whole liver, 11 -HSD1/ 18S expressed as arbitrary units).Carbenoxolone has a significant inhibitory effect on 11 oxo-reductase activity in both rat and human hepatocytes. However, there is clear species-specific regulation of 11 oxo-reductase activity by thyroid hormone (tri-iodothyronine (T 3 )), which increases 11 oxo-reductase activity in rat hepatocytes but has no effect on activity in human hepatocytes, and progesterone which inhibits activity in human hepatocytes, but has no effect on activity in rat hepatocytes. Neither T 3 nor progesterone altered 11 -HSD1 mRNA levels. A series of growth factors (hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, transforming growth factor 1 ) were without effect on 11 oxo-reductase activity in cultured rat hepatocytes.In contrast to homogenates of human liver, cultured hepatocytes express only 11 -HSD oxo-reductase activity. This is inhibited by carbenoxolone and shows speciesspecific regulation by T 3 and progesterone. Growth factors do not appear to regulate activity or expression of 11 -HSD1. The discrepant enzyme activity data and 11 -HSD1 mRNA expression in hepatocytes and whole liver could reflect unstable 11 -HSD1 oxo-reductase activity or, alternatively, an additional 11 -HSD oxo-reductase isoform in cultured hepatocytes.

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A new defect in the peripheral conversion of cortisone to cortisol

Cited by 80 publications

References 5 publications

11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress

11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Regulation of 11 beta-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes

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