Linked Life Data

18095656

Source:http://linkedlifedata.com/resource/pubmed/id/18095656

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2008-2-19
pubmed:abstractText
SPD-304 is a recently discovered small-molecule TNF-alpha antagonist. However, SPD-304 contains a potentially toxic 3-alkylindole moiety. Previous studies on 3-methylindole and the 3-alkylindole-containing drugs zafirlukast and MK-0524 structural analogues found that they were bioactivated by cytochrome P450s through a dehydrogenation process to form 3-methyleneindolenine intermediates that are electrophilic alpha,beta-unsaturated iminium species. These electrophiles could react with protein and/or DNA nucleophilic residues to cause toxicities. In the present study, we found that SPD-304 was bioactivated through a similar dehydrogenation mechanism to produce a similar electrophilic 3-methyleneindolenine intermediate. The electrophile was trapped with nucleophilic glutathione and identified by LC/MS/MS. The iminium or another reactive intermediate also was a mechanism-based inactivator of CYP3A4. The inactivation parameters were K I = 29 microM and k inact = 0.047 min (-1). In addition, SPD-304 was metabolized through hydroxylation, N-dealkylation, and epoxidation pathways, and several metabolites and glutathione adducts were characterized by tandem mass spectrometry. The metabolism profile was also evaluated by in silico molecular docking of SPD-304 into the active site of CYP3A4, which predicted that the dehydrogenation reaction was initiated by 3-methylene C-H atom abstraction at the trifluoromethylphenyl-1 H-indol-3-ylmethyl portion of SPD-304. Hydroxylation of the 6'-methyl of the dimethylchromone portion of SPD-304 was the other major predicted metabolic pathway. The molecular models correlated precisely with experimental metabolic results. In summary, dehydrogenation of SPD-304 may cause toxicities through the formation of electrophilic intermediates and cause drug-drug interactions through CYP3A4 inactivation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
374-85
pubmed:meshHeading
pubmed-meshheading:18095656-Alkylation, pubmed-meshheading:18095656-Chromans, pubmed-meshheading:18095656-Chromatography, High Pressure Liquid, pubmed-meshheading:18095656-Cytochrome P-450 CYP3A, pubmed-meshheading:18095656-Drug Interactions, pubmed-meshheading:18095656-Enzyme Inhibitors, pubmed-meshheading:18095656-Epoxy Compounds, pubmed-meshheading:18095656-Glutathione, pubmed-meshheading:18095656-Humans, pubmed-meshheading:18095656-Hydrogenation, pubmed-meshheading:18095656-Indoles, pubmed-meshheading:18095656-Microsomes, Liver, pubmed-meshheading:18095656-Models, Structural, pubmed-meshheading:18095656-Skatole, pubmed-meshheading:18095656-Spectrometry, Mass, Electrospray Ionization, pubmed-meshheading:18095656-Tandem Mass Spectrometry, pubmed-meshheading:18095656-Tumor Necrosis Factor-alpha
pubmed:year
2008
pubmed:articleTitle
Metabolic activation of a novel 3-substituted indole-containing TNF-alpha inhibitor: dehydrogenation and inactivation of CYP3A4.
pubmed:affiliation
Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Room 201, Salt Lake City, Utah 84112-5820, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural