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KMID : 0379520040200010071
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한국독성학회지
2004 Volume.20 No. 1 p.71 ~ p.82
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Ozone Inhalation with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)- 1-butanone and/or Dibutyl Phthalate Induced Cell Cycle Alterations via Wild-type p53 Instability in B6C3F1 Mice
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Kim Min-Young
Song Kyung-Seuk
Park Gun-Ho
Kim Hyun-Woo
Park Jin-Hong
Kim J.-S.
Jin Hwa
Eu Gook-Jong
Cho Hyun-Sun
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Abstract
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Changes in cell cycle control in the lungs and liver of the B6C3F1 mice (20 males per each group) exposed to ozone (0.5 ppm), 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 1.0 mg/kg), and dibutyl phthalate (DBP, 5,000 ppm) after 52 weeks were examined through Western, Northern blot, and immunohistochemistry based on alterations in protein expression levels of G1/S checkpoints (cyclin D1, cyclin E, and PCNA), G2/M checkpoints (cyclin B1, cyclin G, and cyclin A), negative regulators (p53, p21, GADD45, and p27), and positive regulator (mdm2). Expression levels of cyclins D1, E, G, PCNA, mutant p53, and mdm2 proteins were higher in the lungs and livers treated with combination of toxicants than in those treated with ozone only. Expression levels of the wild-type and mutant p53, p21, GADD45, p27, and mdm2 proteins and mRNAs were higher in toxicant-treated groups than those of the control. Immunohistochemical analysis revealed staining intensities of the PCNA, cyclin D1, c-myc and mdm2 protein- treated lungs and livers were stronger than those of the control group. Our results showed that combined treatment of ozone with NNK/DBP altered the cell cycle control through instability of the wild-type p53 gene. Such pivotal p53-mediated cell cycle alterations may be responsible for the toxicity observed under our experimental condition. These results may be applied to risk assessment of mixture-induced toxicity.
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KEYWORD
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Ozone, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, Dibutyl phthalate, Inhalation.
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