			Home About us Contact

Hydroxysteroid Dehydrogenase Type (hydroxysteroid + dehydrogenase_type)

Distribution by Scientific Domains

Chemistry	83%

Selected Abstracts

Discovery of Adamantyl Ethanone Derivatives as Potent 11,-Hydroxysteroid Dehydrogenase Type,1 (11,-HSD1) Inhibitors

CHEMMEDCHEM, Issue 7 2010
Xiangdong Su Dr.
Abstract 11,-Hydroxysteroid dehydrogenases (11,-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11,-HSD type,1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11,-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11,-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11,-HSD1 with IC50 values in the 50,70,nM range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in,vivo studies. Comparison of the publicly available X-ray crystal structures of human 11,-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor. [source]

Regulated expression by PPAR, and unique localization of 17,-hydroxysteroid dehydrogenase type 11 protein in mouse intestine and liver

FEBS JOURNAL, Issue 18 2007
Yasuhide Yokoi
17,-Hydroxysteroid dehydrogenase type 11 (17,-HSD11) is a member of the short-chain dehydrogenase/reductase family involved in the activation and inactivation of sex steroid hormones. We recently identified 17,-HSD11 as a gene that is efficiently regulated by peroxisome proliferator-activated receptor-, PPAR, in the intestine and the liver [Motojima K (2004) Eur J Biochem271, 4141,4146]. In this study, we characterized 17,-HSD11 at the protein level to obtain information about its physiologic role in the intestine and liver. For this purpose, specific antibodies against 17,-HSD11 were obtained. Western blotting analysis showed that administration of a peroxisome proliferator-activated receptor-, agonist induced 17,-HSD11 protein in the jejunum but not in the colon, and to a much higher extent than in the liver of mice. A subcellular localization study using Chinese hamster ovary cells and green fluorescent protein-tagged 17,-HSD11 showed that it was mostly localized in the endoplasmic reticulum under normal conditions, whereas it was concentrated on lipid droplets when they were induced. A pulse-chase experiment suggested that 17,-HSD11 was redistributed to the lipid droplets via the endoplasmic reticulum. Immunohistochemical analysis using tissue sections showed that 17,-HSD11 was induced mostly in intestinal epithelia and hepatocytes, with heterogeneous localization both in the cytoplasm and in vesicular structures. A subcellular fractionation study of liver homogenates confirmed that 17,-HSD11 was localized mostly in the endoplasmic reticulum when mice were fed a normal diet, but was distributed in both the endoplasmic reticulum and the lipid droplets of which formation was induced by feeding a diet containing a proliferator-activated receptor-, agonist. Taken together, these data indicate that 17,-HSD11 localizes both in the endoplasmic reticulum and in lipid droplets, depending on physiologic conditions, and that lipid droplet 17,-HSD11 is not merely an endoplasmic reticulum contaminant or a nonphysiologically associated protein in the cultured cells, but a bona fide protein component of the membranes of both intracellular compartments. [source]

17, -Hydroxysteroid dehydrogenase type 11 is a major peroxisome proliferator-activated receptor ,-regulated gene in mouse intestine

FEBS JOURNAL, Issue 20 2004
Kiyoto Motojima
In order to study the role of peroxisome proliferator-activated receptor , in mouse intestine, its agonist-induced proteins were identified by peptide mass fingerprinting followed by Northern blot analysis using their cDNAs. One of the most remarkably induced proteins was identified as 17,-hydroxysterol dehydrogenase type 11. Its very rapid induction by various agonists was most efficient in intestine and then in liver. These findings together with recently reported results showing the enzyme family's wide substrate spectrum, including not only glucocorticoids and sex steroids but also bile acids, fatty acids and branched chain amino acids, suggest new roles for both peroxisome proliferator-activated receptor , and 17,-hydroxysterol dehydrogenase type 11 in lipid metabolism and/or detoxification in the intestine. [source]

Regulated expression by PPAR, and unique localization of 17,-hydroxysteroid dehydrogenase type 11 protein in mouse intestine and liver

Single nucleotide polymorphisms of 17,-hydroxysteroid dehydrogenase type 7 gene: Mechanism of estramustine-related adverse reactions?

INTERNATIONAL JOURNAL OF UROLOGY, Issue 10 2009
Takeshi Ozeki
Objectives: To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17,-hydroxysteroid dehydrogenase (HSD17B7) gene. Methods: Luciferase reporter genes containing a 5,-flanking of the HSD17B7 gene, as well as the sequence around the SNP, were transfected into LNCaP and DU145 cells. Then, luciferase assays were carried out. Results: The presence of the G allele resulted in an increase of transcriptional activity derived from the 5,-flanking region of the HSD17B7 gene by 270% and 370% in LNCaP and DU145 cells, respectively. Transcriptional activity of the HSD17B7 gene containing the G allele was higher than that of the C allele. Conclusions: The transcriptional activity of the HSD17B7 gene containing the G allele is higher than that of the C allele. This difference in HSD17B7 expression may regulate the risk of peripheral edema as an adverse reaction induced by estramustine phosphate sodium. [source]

Differential protein expression on the cell surface of colorectal cancer cells associated to tumor metastasis

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2010
Jose Luis Luque-García
Abstract Progression to metastasis is the critical point in colorectal cancer (CRC) survival. However, the proteome associated to CRC metastasis is very poorly understood at the moment. In this study, we used stable isotope labeling by amino acids in cell culture to compare two CRC cell lines: KM12C and KM12SM, representing poorly versus highly metastatic potential, to find and quantify the differences in protein expression, mostly at the cell surface level. After biotinylation followed by affinity purification, membrane proteins were separated by SDS-PAGE and analyzed using nanoflow LC-ESI-LTQ. A total of 291 membrane and membrane-associated proteins were identified with a p value<0.01, from which 60 proteins were found to be differentially expressed by more than 1.5-fold. We identified a number of cell signaling, CDs, integrins and other cell adhesion molecules (cadherin 17, junction plakoglobin (JUP)) among the most deregulated proteins. They were validated by Western blot, confocal microscopy and flow cytometry analysis. Immunohistochemical analysis of paired tumoral samples confirmed that these differentially expressed proteins were also altered in human tumoral tissues. A good correlation with a major abundance in late tumor stages was observed for JUP and 17-,-hydroxysteroid dehydrogenase type 8 (HSD17B8). Moreover, the combined increase in JUP, occludin and F11 receptor expression together with cadherin 17 expression could suggest a reversion to a more epithelial phenotype in highly metastatic cells. Relevant changes were observed also at the metabolic level in the pentose phosphate pathway and several amino acid transporters. In summary, the identified proteins provide us with a better understanding of the events involved in liver colonization and CRC metastasis. [source]