Source:http://linkedlifedata.com/resource/pubmed/id/19010388
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1-2
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pubmed:dateCreated |
2009-2-23
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pubmed:abstractText |
Intracellular glucocorticoid reactivation is catalyzed by 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which functions predominantly as a reductase in cells expressing hexose-6-phosphate dehydrogenase (H6PDH). We recently showed that the ratios of cortisone to cortisol and 7-keto- to 7-hydroxy-neurosteroids are regulated by 11beta-HSD1 and very much depend on coexpression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11beta-HSD1-dependent interconversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11beta-HSD1 or coexpressing 11beta-HSD1 and H6PDH, we observed significant differences of 11beta-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11beta-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells overexpressing 11beta-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11beta-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11beta-HSD1 reductase activity in differentiated THP-1 macrophages (IC(50) 8.1+/-0.9microM). 7-Keto-DHEA but not 7-KC inhibited 11beta-HSD1 in HEK-293 cell lysates. In conclusion, cellular factors such as H6PDH can significantly modulate the effect of inhibitors and alternative 7-oxygenated substrates on intracellular glucocorticoid availability.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/11-beta-Hydroxysteroid...,
http://linkedlifedata.com/resource/pubmed/chemical/7-ketocholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Carbohydrate Dehydrogenases,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Extracts,
http://linkedlifedata.com/resource/pubmed/chemical/Corticosterone,
http://linkedlifedata.com/resource/pubmed/chemical/Dehydroepiandrosterone,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/HSD11B1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Ketocholesterols,
http://linkedlifedata.com/resource/pubmed/chemical/galactose-6-phosphate dehydrogenase
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0303-7207
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
25
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pubmed:volume |
301
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
117-22
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pubmed:meshHeading |
pubmed-meshheading:19010388-11-beta-Hydroxysteroid Dehydrogenase Type 1,
pubmed-meshheading:19010388-Animals,
pubmed-meshheading:19010388-Carbohydrate Dehydrogenases,
pubmed-meshheading:19010388-Cell Extracts,
pubmed-meshheading:19010388-Cell Line,
pubmed-meshheading:19010388-Corticosterone,
pubmed-meshheading:19010388-Dehydroepiandrosterone,
pubmed-meshheading:19010388-Enzyme Inhibitors,
pubmed-meshheading:19010388-Humans,
pubmed-meshheading:19010388-Ketocholesterols,
pubmed-meshheading:19010388-Macrophages,
pubmed-meshheading:19010388-Mice,
pubmed-meshheading:19010388-Models, Molecular,
pubmed-meshheading:19010388-Substrate Specificity
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pubmed:year |
2009
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pubmed:articleTitle |
Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11beta-hydroxysteroid dehydrogenase 1.
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pubmed:affiliation |
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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