Linked Life Data

9215804

Source:http://linkedlifedata.com/resource/pubmed/id/9215804

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1997-9-5
pubmed:abstractText
Micronucleus formation initiated by benzo[a]pyrene (B[a]P) and related xenobiotics is widely believed to reflect potential carcinogenic initiation, yet neither a dependence upon bioactivation nor the critical enzymes have been demonstrated. Using rat skin fibroblasts, protein oxidation (carbonyl formation) and content of prostaglandin H synthase (PHS) and cytochrome P4501A1 (CYP1A1) protein were determined by Western blot/immunodetection with enhanced chemiluminescence. DNA oxidation as 8-hydroxy-2'-deoxyguanosine formation was quantified using high-performance liquid chromatography with electrochemical detection. Fibroblast CYP1A1 activity assessed as ethoxyresorufin-O-deethylase was not detectable, and even CYP1A1 protein was measurable only after induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, TCDD additionally induced prostaglandin H synthase (PHS), which also was detectable constitutively. B[a]P 10 microM initiated the oxidation of DNA and protein, and the formation of micronuclei, all of which were enhanced over 2-fold by the dual CYP1A1/PHS inducer TCDD 10 nM, as well as by other PHS inducers, 12-O-tetradecanoylphorbol-13-acetate 1 microM and interleukin-1alpha 0.625 or 1.25 ng/ml, that do not induce CYP1A1 (p < .05). Conversely, B[a]P target oxidation and micronucleus formation were abolished by 1-aminobenzotriazole 1 mM (p < .05), which was a potent inhibitor of both peroxidases and P450. These results provide the first direct evidence that B[a]P-initiated micronucleus formation, like carcinogenic initiation, requires enzymatic bioactivation, and that peroxidase-dependent, reactive oxygen species-mediated oxidation of DNA, and possibly protein, constitutes a molecular mechanism of initiation in uninduced cells. Induction of either CYP1A1 or peroxidases such as PHS substantially enhances this genotoxic initiation, which may reflect cancer risk.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0891-5849
pubmed:author
pubmed:issnType
Print
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
579-96
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:9215804-Animals, pubmed-meshheading:9215804-Benzo(a)pyrene, pubmed-meshheading:9215804-Cell Nucleus, pubmed-meshheading:9215804-Chromatography, High Pressure Liquid, pubmed-meshheading:9215804-Cytochalasin B, pubmed-meshheading:9215804-Cytochrome P-450 CYP1A1, pubmed-meshheading:9215804-Cytochrome P-450 Enzyme System, pubmed-meshheading:9215804-DNA, pubmed-meshheading:9215804-Enzyme Inhibitors, pubmed-meshheading:9215804-Fibroblasts, pubmed-meshheading:9215804-Male, pubmed-meshheading:9215804-Mice, pubmed-meshheading:9215804-Mice, Inbred C57BL, pubmed-meshheading:9215804-Microsomes, Liver, pubmed-meshheading:9215804-Oxidation-Reduction, pubmed-meshheading:9215804-Peroxidase, pubmed-meshheading:9215804-Proteins, pubmed-meshheading:9215804-Rats, pubmed-meshheading:9215804-Rats, Wistar, pubmed-meshheading:9215804-Tetrachlorodibenzodioxin
pubmed:year
1997
pubmed:articleTitle
Peroxidase-dependent bioactivation and oxidation of DNA and protein in benzo[a]pyrene-initiated micronucleus formation.
pubmed:affiliation
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't