Linked Life Data

16339391

Source:http://linkedlifedata.com/resource/pubmed/id/16339391

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2006-2-23
pubmed:abstractText
Tibolone [[7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is used to treat climacteric symptoms and prevent osteoporosis. It exerts tissue-selective effects via site-specific metabolism into 3alpha- and 3beta-hydroxymetabolites and a Delta4-isomer. Recombinant human cytosolic aldo-keto reductases 1C1 and 1C2 (AKR1C1 and AKR1C2) produce 3beta-hydroxytibolone, and the liver-specific AKR1C4 produces predominantly 3alpha-hydroxytibolone. These observations may account for the appearance of 3beta-hydroxytibolone in target tissues and 3alpha-hydroxytibolone in the circulation. Using liver autopsy samples (which express AKR1C1-AKR1C4), tibolone was reduced via 3alpha- and 3beta-hydroxysteroid dehydrogenase (HSD) activity. 3beta-Hydroxytibolone was exclusively formed in the cytosol and was inhibited by the AKR1C2-specific inhibitor 5beta-cholanic acid-3alpha, 7alpha-diol. The cytosolic formation of 3alpha-hydroxytibolone was inhibited by an AKR1C4-selective inhibitor, phenolphthalein. The ratio of these stereoisomers was 4:1 in favor of 3beta-hydroxytibolone. In HepG2 cell cytosol and intact cells (which do not express AKR1C4), tibolone was exclusively reduced to 3beta-hydroxytibolone and was blocked by the AKR1C1-AKR1C3 inhibitor flufenamic acid. In primary hepatocytes (which express AKR1C1-AKR1C4), time-dependent reduction of tibolone into 3beta- and 3alpha-hydroxytibolone was observed again in a 4:1 ratio. 3beta-HSD activity was inhibited by both 5beta-cholanic acid-3alpha,7alpha-diol and flufenamic acid, implicating a role for AKR1C2 and AKR1C1. By contrast, the formation of 3alpha-hydroxytibolone was exclusively inhibited by phenolphthalein implicating AKR1C4 in this reaction. 3beta- and 3alpha-Hydroxytibolone were rapidly metabolized into polar metabolites (>85%). The formation of minor amounts of tibolone was also observed followed by AKR1C-catalyzed epimerization. The low hepatic formation of 3alpha-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3alpha-HSD.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/17-Hydroxysteroid Dehydrogenases, http://linkedlifedata.com/resource/pubmed/chemical/20-Hydroxysteroid Dehydrogenases, http://linkedlifedata.com/resource/pubmed/chemical/3 (or 17)-beta-hydroxysteroid..., http://linkedlifedata.com/resource/pubmed/chemical/3 alpha-beta, 20..., http://linkedlifedata.com/resource/pubmed/chemical/3-Hydroxysteroid Dehydrogenases, http://linkedlifedata.com/resource/pubmed/chemical/AKR1C2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/AKR1C3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Bile Acids and Salts, http://linkedlifedata.com/resource/pubmed/chemical/Flufenamic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxyprostaglandin Dehydrogenases, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxysteroid Dehydrogenases, http://linkedlifedata.com/resource/pubmed/chemical/Norpregnenes, http://linkedlifedata.com/resource/pubmed/chemical/Oxidoreductases, http://linkedlifedata.com/resource/pubmed/chemical/Phenolphthalein, http://linkedlifedata.com/resource/pubmed/chemical/tibolone, http://linkedlifedata.com/resource/pubmed/chemical/trans-1,2-dihydrobenzene-1,2-diol...
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
316
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1300-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily.
pubmed:affiliation
Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't