The 11β‐Hydroxysteroid Dehydrogenase System, A Determinant of Glucocorticoid and Mineralocorticoid Action

Uct., Oppermann; Persson, Bengt; Jörnvall, Hans

doi:10.1111/j.1432-1033.1997.00365.x

Cited by 64 publications

(16 citation statements)

References 27 publications

(14 reference statements)

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“…This was not an unexpected finding, since 11b-HSD-I is involved in the metabolism of metyrapone, reducing it to metyrapol (41). The inhibitory mechanism is, therefore, probably that of substrate competition.…”

Section: Discussionmentioning

confidence: 81%

In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I

Diederich

Großmann²,

Hanke³

et al. 2000

European Journal of Endocrinology

105

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Objective: Selective inhibitors of 11b-hydroxysteroid-dehydrogenase type I may be of therapeutical interest for two reasons: i) 9a-Fluorinated 11-dehydrosteroids like 11-dehydro-dexamethasone (DH-D) are rapidly activated by human kidney 11b-hydroxysteroid-dehydrogenase type II (11b-HSD-II) to dexamethasone (D). If the same reaction by hepatic 11b-HSD-I could be selectively inhibited, DH-D could be used for selective renal immunosuppressive therapy. ii) Reduction of cortisone to cortisol in the liver may increase insulin resistance in type 2 diabetes mellitus, and inhibition of the enzyme may lead to a decrease in gluconeogenesis.Therefore, we characterized the metabolism of DH-D by human hepatic 11b-HSD-I and tried to find a selective inhibitor of this isoenzyme. Methods: For kinetic analysis of 11b-HSD-I, we used microsomes prepared from unaffected parts of liver segments, resected because of hepatocarcinoma or metastatic disease. For inhibition experiments, we also tested 11b-HSD-II activity with human kidney cortex microsomes. The inhibitory potency of several compounds was evaluated for oxidation and reduction in concentrations from 10 ¹9 to 10 ¹5 mol/l. Results: Whereas D was not oxidized by human liver microsomes at all, cortisol was oxidized to cortisone with a maximum velocity (V max ) of 95 pmol/mg per min. The reduction of DH-D to D (V max = 742 pmol/ mg per min, Michaelis-Menten constant (K m ) = 1.6 mmol/l) was faster than that of cortisone to cortisol (V max =187 pmol/mg per min). All reactions tested in liver microsomes showed the characteristics of 11b-HSD-I: K m values in the micromolar range, preferred cosubstrate NADP(H), no product inhibition. Of the substances tested for inhibition of 11b-HSD-I and -II, chenodeoxycholic acid was the only one that selectively inhibited 11b-HSD-I (IC 50 for reduction: 2.8 × 10 ¹6 mol/l, IC 50 for oxidation: 4.4 × 10 ¹6 mol/l), whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11b-HSD-II. Metyrapone, which is reduced to metyrapol by hepatic 11b-HSD-I, inhibited steroid reductase activity of 11b-HSD-I and -II and oxidative activity of 11b-HSD-II. These findings can be explained by substrate competition for reductase reactions and by product inhibition of the oxidation, which is a well-known characteristic of 11b-HSD-II. Conclusions: Our in vitro results may offer a new concept for renal glucocorticoid targeting. Oral administration of small amounts of DH-D (low substrate affinity for 11b-HSD-I) in combination with chenodeoxycholic acid (selective inhibition of 11b-HSD-I) may prevent hepatic first pass reduction of DH-D, thus allowing selective activation of DH-D to D by the high affinity 11b-HSD-II in the kidney. Moreover, selective inhibitors of the hepatic 11b-HSD-I, like chenodeoxycholic acid, may become useful in the therapy of patients with hepatic insulin resistance including diabetes mellitus type II, because cortisol enhances gluconeogenesis.

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Section: Discussionmentioning

confidence: 81%

In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I

Diederich

Großmann²,

Hanke³

et al. 2000

European Journal of Endocrinology

105

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“…Detoxification often occurs in two phases; in phase I, the initial compound is transformed into a more reactive species. A variety of different chemical transformations are involved, including redox reactions catalyzed by enzymes of the cytochrome P450 superfamily (4,5) and members of the short chain dehydrogenase/reductase (SDR) 1 family (6). Phase II reactions consist in the addition, either to a product of a phase I reaction or directly to many toxic chemicals, of a highly polar group such as UDP-glucuronosyl (catalyzed by UDP-glucuronosyltransferases) (2) or glutathione (catalyzed by glutathione S-transferases (7).…”

mentioning

confidence: 99%

Preferential Expression of Biotransformation Enzymes in the Olfactory Organs of Drosophila melanogaster, the Antennae

Wang¹,

Hasan

Pikielny³

1999

Journal of Biological Chemistry

113

102

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Biotransformation enzymes have been found in the olfactory epithelium of vertebrates. We now show that in Drosophila melanogaster, a UDP-glycosyltransferase (UGT), as well as a short chain dehydrogenase/reductase and a cytochrome P450 are expressed specifically or preferentially in the olfactory organs, the antennae. The evolutionarily conserved expression of biotransformation enzymes in olfactory organs suggests that they play an important role in olfaction. In addition, we describe five Drosophila UGTs belonging to two families. All five UGTs contain a putative transmembrane domain at their C terminus as is the case for vertebrate UGTs where it is required for enzymatic activity. The primary sequence of the C terminus, including part of the transmembrane domain, differs between the two families but is highly conserved not only within each Drosophila family, but also between the members of one of the Drosophila families and vertebrate UGTs. The partial overlap of the conserved primary sequence with the transmembrane domain suggests that this part of the protein is involved in specific interactions occurring at the membrane surface. The presence of different C termini in the two Drosophila families suggests that they interact with different targets, one of which is conserved between Drosophila and vertebrates.

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“…5,6) The microsomal CR is dimeric and identical to 11b-hydroxysteroid dehydrogenase type 1. 7) In addition, several cytosolic enzymes that metabolize endogenous substrates exhibit CR activity. These include tetrameric dicarbonyl/L-xylulose reductase, 8) dimeric sepiapterin reductase, 9) dimeric aflatoxin B 1 aldehyde reductase, 10) monomeric 3a-and 17b-hydroxysteroid dehydrogenases 11,12) and monomeric prostaglandin F synthase.…”

mentioning

confidence: 99%

Characterization of an Oligomeric Carbonyl Reductase of Dog Liver: Its Identity with Peroxisomal Tetrameric Carbonyl Reductase

Endo

Matsunaga

Nagano

et al. 2007

Biological & Pharmaceutical Bulletin

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The 11β‐Hydroxysteroid Dehydrogenase System, A Determinant of Glucocorticoid and Mineralocorticoid Action

Cited by 64 publications

References 27 publications

In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I

In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I

Preferential Expression of Biotransformation Enzymes in the Olfactory Organs of Drosophila melanogaster, the Antennae

Characterization of an Oligomeric Carbonyl Reductase of Dog Liver: Its Identity with Peroxisomal Tetrameric Carbonyl Reductase

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