Effect of chenodeoxycholic acid on 11$beta;-hydroxysteroid dehydrogenase in various target tissues*1

Morris, Devin B

doi:10.1016/s0026-0495(04)00067-8

Cited by 2 publications

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“…Diederich et al (2000) suggested that CDCA acts as a selective 11 -HSD1 inhibitor, with an IC 50 of 2·8 µM obtained with human hepatic microsomes. Morris et al (2004) reported inhibition of the dehydrogenase activity of 11 -HSD1 with IC 50 values of 0·2-7 µM, but only 37-200 µM for the oxoreductase activity in rat liver microsomes. They found weak inhibition of 11 -HSD2 from sheep kidney, with an IC 50 of 70 µM.…”

Section: Discussionmentioning

confidence: 99%

Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Arampatzis¹,

Kadereit²,

Schuster³

et al. 2005

Journal of Molecular Endocrinology

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Abstract11 -Hydroxysteroid dehydrogenase type 1 (11 -HSD1), catalyzing the intracellular activation of cortisone to cortisol, is currently considered a promising target to treat patients with metabolic syndrome; hence, there is considerable interest in the development of selective inhibitors. For preclinical tests of such inhibitors, the characteristics of 11 -HSD1 from the commonly used species have to be known. Therefore, we determined differences in substrate affinity and inhibitor effects for 11 -HSD1 from six species. The differences in catalytic activities with cortisone and 11-dehydrocorticosterone were rather modest. Human, hamster and guinea-pig 11 -HSD1 displayed the highest catalytic efficiency in the oxoreduction of cortisone, while mouse and rat showed intermediate and dog the lowest activity. Murine 11 -HSD1 most efficiently reduced 11-dehydrocorticosterone, while the enzyme from dog showed lower activity than those from the other species. 7-Ketocholesterol (7KC) was stereospecifically converted to 7 -hydroxycholesterol by recombinant 11 -HSD1 from all species analyzed except hamster, which showed a slight preference for the formation of 7 -hydroxycholesterol. Importantly, guinea-pig and canine 11 -HSD1 displayed very low 7-oxoreductase activities. Furthermore, we demonstrate significant species-specific variability in the potency of various 11 -HSD1 inhibitors, including endogenous compounds, natural chemicals and pharmaceutical compounds. The results suggest significant differences in the three-dimensional organization of the hydrophobic substrate-binding pocket of 11 -HSD1, and they emphasize that species-specific variability must be considered in the interpretation of results obtained from different animal experiments. The assessment of such differences, by cell-based test systems, may help to choose the appropriate animal for safety and efficacy studies of novel potential drug candidates.

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Section: Discussionmentioning

confidence: 99%

Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Arampatzis¹,

Kadereit²,

Schuster³

et al. 2005

Journal of Molecular Endocrinology

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“…Most widely used are glycyrrhetinic acid and its hemisuccinate ester carbenoxolone, originally developed for the treatment of peptic ulcer. Other reported natural compound to inhibit 11 -HSD enzymes include flavonoids such as naringenin [143][144][145] or endogenous steroids such as pregnane derivatives [146] or bile acids like chenodeoxycholic acid [147,148]. However, all these compounds are characterized by a lack of selectivity, fairly low efficacy, are not easily amenable to combinatorial chemistry, show unfavorable pharmacochemical properties, or a combination of all.…”

Section: Structure Function Relationships: Development Of Selective 1mentioning

confidence: 99%

Type 1 11 β-hydroxysteroid Dehydrogenase as Universal Drug Target in Metabolic Diseases?

Oppermann

2006

EMIDDT

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Glucocorticoid hormones play essential roles in adaptation to stress, regulation of metabolism and inflammatory responses. Their effects primarily depend on their binding to intracellular receptors leading to altered target gene transcription as well as on cell-type specific biotransformation between 11beta-hydroxy glucocorticoids and their 11-oxo metabolites. The latter effect is accomplished by two different 11beta-hydroxysteroid dehydrogenase isozymes, constituting a shuttle system between the receptor ligand cortisol and its non-binding precursor cortisone. Whereas the type 1 enzyme (11beta-HSD1) is in vitro a NADP(H)- dependent bidirectional enzyme, it reduces in most instances in vivo cortisone to active cortisol. The type 2 enzyme is an exclusive NAD+ dependent dehydrogenase of glucocorticoids, thus "protecting" the mineralocorticoid receptor against illicit occupation by cortisol. Inhibition of tissue-specific glucocorticoid activation by 11beta-HSD1 constitutes a promising target in the treatment of metabolic and cardiovascular diseases. Pharmacological inhibition leads in animal models to lowered hepatic glucose production and increased insulin sensitivity, the primary goals in therapy of diabetes mellitus. Importantly, 11beta-HSD1 activity appears to be intrinsically linked to all features of the metabolic syndrome, which could at least in animal experiments be modulated by use of synthetic selective inhibitors. Importantly, these features include not only insulin resistance but also dyslipidemia, obesity and arterial hypertension. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, due to the role of glucocorticoids and cellular activation by 11beta-HSD1 in these pathologies. The recent development of specific 11beta-HSD1 inhibitors coupled with advances on structural knowledge and regulation of the 11beta-HSD1 target has undoubtedly promoted the understanding of glucocorticoid control of metabolic regulation. Taken together, it appears that inhibitors against 11beta-HSD1 constitute a promising avenue for novel treatment strategies against the underlying causes of cardiovascular and other metabolic diseases.

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Effect of chenodeoxycholic acid on 11$beta;-hydroxysteroid dehydrogenase in various target tissues*1

Cited by 2 publications

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Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Type 1 11 β-hydroxysteroid Dehydrogenase as Universal Drug Target in Metabolic Diseases?

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Effect of chenodeoxycholic acid on 11$beta;-hydroxysteroid dehydrogenase in various target tissues*1

Cited by 2 publications

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Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species

Type 1 11 &#946;-hydroxysteroid Dehydrogenase as Universal Drug Target in Metabolic Diseases?

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Type 1 11 β-hydroxysteroid Dehydrogenase as Universal Drug Target in Metabolic Diseases?