Linked Life Data

10366544

Source:http://linkedlifedata.com/resource/pubmed/id/10366544

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1999-6-24
pubmed:abstractText
N-Nitrosodimethylamine (NDMA) is an acute hepatotoxin and potent carcinogen. The metabolic activation of NDMA to reactive metabolites is a critical step for the expression of its toxic and carcinogenic potential. We have previously demonstrated a strong correlation between methylation of cellular macromolecules and NDMA-mediated cytotoxicity, and we have demonstrated that reactive oxygen species may partially contribute to the toxic effects in P450 2E1-expressing cells. The mode of cell death in NDMA-treated monolayer cultures exhibited the following characteristics: (i) condensation of nuclear chromatin as demonstrated by using Hoechst 33258 staining, (ii) DNA fragmentation as detected by combining pulsed field and conventional agarose gel electrophoresis, and (iii) DNA double strand breaks determined by using the in situ terminal deoxynucleotidyl transferase assay and flow cytometric analysis. These results indicate that reactive metabolites of NDMA trigger activation of the signal pathway for apoptotic cell death in these P450-expressing cells. The NDMA-mediated cell death was partially prevented by the endonuclease inhibitor, aurintricarboxylic acid, as well as the caspase inhibitors, acetyl-Asp-Glu-Val-Asp-CHO and acetyl-Tyr-Val-Ala-Asp-CHO. The cell cycle distribution was altered in NDMA-treated cells resulting in an increase in the G2/M phase and a decrease in the G1 phase. Our results suggest that DNA degradation, the inability to complete DNA repair, the biochemical events associated with G2/M arrest, and the process of apoptotic death all result from P450 2E1-catalyzed metabolism of NDMA.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0041-008X
pubmed:author
pubmed:copyrightInfo
Copyright 1999 Academic Press.
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
157
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
117-24
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10366544-Apoptosis, pubmed-meshheading:10366544-Aurintricarboxylic Acid, pubmed-meshheading:10366544-Caspases, pubmed-meshheading:10366544-Cell Cycle, pubmed-meshheading:10366544-Cell Line, pubmed-meshheading:10366544-Cell Nucleus, pubmed-meshheading:10366544-Cell Survival, pubmed-meshheading:10366544-Chromatin, pubmed-meshheading:10366544-Cytochrome P-450 CYP2E1, pubmed-meshheading:10366544-DNA Damage, pubmed-meshheading:10366544-DNA Fragmentation, pubmed-meshheading:10366544-DNA Repair, pubmed-meshheading:10366544-Dimethylnitrosamine, pubmed-meshheading:10366544-Dose-Response Relationship, Drug, pubmed-meshheading:10366544-Electrophoresis, Gel, Pulsed-Field, pubmed-meshheading:10366544-Endonucleases, pubmed-meshheading:10366544-Flow Cytometry, pubmed-meshheading:10366544-Humans, pubmed-meshheading:10366544-In Situ Nick-End Labeling, pubmed-meshheading:10366544-Reactive Oxygen Species
pubmed:year
1999
pubmed:articleTitle
N-Nitrosodimethylamine-mediated cytotoxicity in a cell line expressing P450 2E1: evidence for apoptotic cell death.
pubmed:affiliation
Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan, 48109-0632, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.