Linked Life Data

18370414

Source:http://linkedlifedata.com/resource/pubmed/id/18370414

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2008-4-22
pubmed:abstractText
Nitric oxide synthases (NOSs) are flavohemeproteins that catalyze the oxidation of L-arginine to L-citrulline with formation of the signaling molecule nitric oxide (NO). In addition to their fundamental role in NO biosynthesis, NOSs are also involved in the formation of reactive oxygen and nitrogen species (RONS) and in the interactions with some drugs. 5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) is a dinitroaromatic compound tested as an antitumor prodrug that requires reduction to the 2- and 4-hydroxylamines to be cytotoxic. Here, we studied the interaction of neuronal, inducible, and endothelial NOSs with CB1954. Our results showed that the three purified recombinant NOSs selectively reduced the 4-nitro group of CB1954 to the corresponding 4-hydroxylamine with minimal 2-nitroreduction. Little further two-electron reduction of the hydroxylamines to the corresponding 2- and 4-amines was observed. The reduction of CB1954 catalyzed by the neuronal NOS (nNOS) was inhibited by O 2 and a flavin/NADPH binding inhibitor, diphenyliodonium (DPI), but insensitive to the addition of the heme ligands imidazole and carbon monoxide and of l-arginine analogues. This reduction proceeded with intermediate formation of a nitro-anion free radical observed by EPR. Involvement of the reductase domain of nNOS in the reduction of CB1954 was confirmed by the ability of the isolated reductase domain of nNOS to catalyze the reaction and by the stimulating effect of Ca (2+)/calmodulin on the accumulation of 4- and 2-hydroxylamines. The recombinant inducible and endothelial NOS isoforms reduced CB1954 with lower activity but higher selectivity for the cytotoxic 4-hydroxylamine compared with nNOS. Finally, CB1954 did not modify the formation of l-citrulline and RONS catalyzed by nNOS. Our results show that all three NOS isoforms are involved in the nitroreduction of CB1954, with predominant formation of the cytotoxic 4-hydroxylamine derivative. This nitroreduction could be of interest for the selective activation of prodrugs by NOSs overexpressed in tumor cells.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
836-43
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Metabolic activation of the antitumor drug 5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by NO synthases.
pubmed:affiliation
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université R. Descartes, UMR 8601 CNRS, 45 rue des Saints-Pères, 75270 Paris cedex 06, France.
pubmed:publicationType
Journal Article