Linked Life Data

8442764

Source:http://linkedlifedata.com/resource/pubmed/id/8442764

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1993-3-26
pubmed:abstractText
In the present study it has been shown that ethacrynic acid can inhibit glutathione S-transferase (GST) of the pi-class irreversibly. [14C]Ethacrynic acid, 0.8 nmol/nmol human P1-1 and 0.8 nmol/nmol rat GST 7-7 could be incorporated, resulting in 65-93% inhibition of the activity towards 1-chloro-2,4-dinitrobenzene (CDNB). Isoenzymes of the alpha- and mu-class also bound [14C]ethacrynic acid, however without loss of catalytic activity. Incorporation ranged from 0.3 to 0.6 and 0.2 nmol/nmol enzyme for the mu- and alpha-class GST isoenzymes, respectively. For all isoenzymes, incorporation of [14C]ethacrynic acid could be prevented by preincubation with tetrachloro-1,4-benzoquinone, suggesting, that a cysteine residue is the target site. Protection of GST P1-1 against inhibition by ethacrynic acid by the substrate analog S-hexylglutathione, indicates an active site-directed modification. The monobromo and dibromo dihydro derivatives of ethacrynic acid were synthesized in an effort to produce more reactive compounds. The monobromo derivative did not exhibit enhanced irreversible inhibitory capacity. However, the dibromo dihydro derivative inhibited both human and rat GST isoenzymes of the pi-class very efficiently, resulting in 90-96% inhibition of the activity towards CDNB. Interestingly, this compound is also a powerful irreversible inhibitor of the mu-class GST isoenzymes, resulting in 52-70% inhibition. The two bromine atoms only marginally affect the strong (reversible) competitive inhibitory capacity of ethacrynic acid, with IC50 (microM) of 0.4-0.6 and 4.6-10 for the mu- and pi-class GST isoenzymes, respectively.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
633-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
Isoenzyme selective irreversible inhibition of rat and human glutathione S-transferases by ethacrynic acid and two brominated derivatives.
pubmed:affiliation
Department of Biological Toxicology, TNO Toxicology and Nutrition Institute, Zeist, The Netherlands.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't