Document Detail

Role of COX-2 in the bioactivation of methylenedianiline and in its proliferative effects in vascular smooth muscle cells.
MedLine Citation:
PMID:  21720929     Owner:  NLM     Status:  MEDLINE    
4,4'-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane foams and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased the rates of proliferation in a manner that was inhibited by co-treatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity, and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased the rates of proliferation in VSMC isolated from wild-type but not COX-2 (-/-) mice. Paradoxically, treatment with DAPM reduced the cellular production of PGE(2) and PGF(2α), but dose-dependently increased the COX-2 protein levels. Covalent binding of [(14)C]-DAPM to VSMC biomolecules was greater in wild-type than in COX-2 (-/-) cells. However, covalent binding of [(14)C]-DAPM was not altered by co-treatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM's mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted.
Valeria Y Hebert; Brandon Chad Jones; Randy C Mifflin; Tammy R Dugas
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cardiovascular toxicology     Volume:  11     ISSN:  1559-0259     ISO Abbreviation:  Cardiovasc. Toxicol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-02     Completed Date:  2012-02-21     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  101135818     Medline TA:  Cardiovasc Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  316-24     Citation Subset:  IM    
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MeSH Terms
Aniline Compounds / pharmacokinetics,  toxicity*
Carcinogens / pharmacokinetics,  toxicity*
Cell Proliferation / drug effects
Cells, Cultured
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / biosynthesis*
Cyclooxygenase 2 Inhibitors / pharmacology
Membrane Proteins / metabolism
Muscle, Smooth, Vascular / drug effects*,  enzymology
Pulmonary Artery / drug effects,  metabolism
Pyrazoles / pharmacology
Rats, Sprague-Dawley
Sulfonamides / pharmacology
Tunica Media / drug effects,  metabolism
Grant Support
Reg. No./Substance:
0/Aniline Compounds; 0/Carcinogens; 0/Cyclooxygenase 2 Inhibitors; 0/Membrane Proteins; 0/Pyrazoles; 0/Sulfonamides; 169590-42-5/celecoxib; EC 1; EC 2; EC protein, rat; EC protein, rat; GG5LL7OBZC/4,4'-diaminodiphenylmethane

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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