Document Detail

Effects of cadmium(II) on (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-induced DNA damage response in human fibroblasts and DNA repair: a possible mechanism of cadmium's cogenotoxicity.
MedLine Citation:
PMID:  15025498     Owner:  NLM     Status:  MEDLINE    
Cadmium, a widespread environmental pollutant and a cigarette smoke constituent, enhances the genotoxicity of benzo[a]pyrene (BP). The mechanism(s) underlying the potentiation of BP-induced genotoxicity by Cd2+ is not clearly understood. Our studies of the effects of noncytotoxic concentrations of Cd2+ on the levels of p53 and p21 in (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)-treated human fibroblasts showed that Cd2+ decreased BPDE-induced p21 levels in a dose-dependent manner whereas p53 accumulation is attenuated only at higher noncytotoxic concentrations of cadmium. These findings suggest that both the activity and the accumulation of p53 in response of BPDE treatment are inhibited by Cd2+ although the possibility of p53-independent p21 transactivation cannot be ruled out. Exposure of synchronized human fibroblast cells to 0.5 microM of BPDE caused 72% of the cells remaining in G1 phase as compared to 52% in the case of untreated cells. Treatment of the cells with CdCl2 prior to exposing them to BPDE caused a decrease in the G1 population (72 to 54%) in a dose-dependent manner. An in vitro repair assay of BPDE-damaged pUC18 plasmid DNA using untreated and cadmium-treated nucleotide excision repair (NER) proficient HeLa extract showed that cadmium impaired the ability of HeLa cell extract to repair BPDE-damaged pUC18 DNA. Our findings indicate that cadmium not only inhibits NER pathway-dependent repair of BPDE-damaged DNA but also impairs p53 and p21 responses and overrides BPDE-induced G1-S cell cycle arrest. The effect of cadmium on these processes may explain, at least partly, the potentiating effect of the metal on the genotoxicity of BP.
Jagat J Mukherjee; Suresh K Gupta; Subodh Kumar; Harish C Sikka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  17     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-03-17     Completed Date:  2004-10-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  287-93     Citation Subset:  IM    
Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222, USA.
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MeSH Terms
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / toxicity*
Cadmium / toxicity*
Cell Survival / drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / metabolism
DNA / drug effects
DNA Damage*
DNA Repair*
Dose-Response Relationship, Drug
Drug Synergism
Environmental Pollutants / toxicity*
Fibroblasts / drug effects*,  metabolism,  pathology
Interphase / drug effects
Mutagens / toxicity*
Tumor Suppressor Protein p53 / metabolism
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Environmental Pollutants; 0/Mutagens; 0/Tumor Suppressor Protein p53; 55097-80-8/7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; 7440-43-9/Cadmium; 9007-49-2/DNA

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