Abstract:
:The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1, on the catalytic activities and total content of hepatic P450 was determined in vivo and in vitro. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 h postdosing, and total P450 content and the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, P450 2E1, and P450 3A were determined. The lowest dose of DCE that yielded maximal inactivation of P450 2E1 was found to be 100 mg/kg. Significant decreases in total content of P450 or the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, and P450 3A were not observed during the 24 h following administration of DCE (100 mg/kg ip), but P450 2E1 activity was diminished about 65% at 2 and 5 h after DCE treatment and returned to control levels at 24 h. Additionally, there was little or no significant effect on the activities of hepatic cytosolic alcohol dehydrogenase or mitochondrial or microsomal aldehyde dehydrogenases 5 h postdosing. DCE showed the same selectivity for P450 inactivation in vitro, and P450 2E1 activity was inhibited by >80% without affecting the other isozymes. However, DCE (5 mM) also proved to be a good competitive inhibitor of the probe activities of P450 1A2 and P450 2C6. The in vivo inhibition of P450 2E1 was accompanied by decreases in the levels of the immunoreactive protein, and an additional immunoreactive band appeared at ca. 30 kDa in the Western blot of microsomes from DCE-treated rats, possibly arising from proteolytic degradation of P450 2E1 protein after covalent modification by the inhibitor. DCE is an effective, relatively nontoxic inhibitor of P450 2E1 in vivo and in vitro that has greater selectivity than other agents currently used.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Mathews JM,Etheridge AS,Raymer JH,Black SR,Pulliam DW Jr,Bucher JRdoi
10.1021/tx970227gsubject
Has Abstractpub_date
1998-07-01 00:00:00pages
778-85issue
7eissn
0893-228Xissn
1520-5010pii
tx970227gjournal_volume
11pub_type
杂志文章abstract::To investigate the biological effects of the O(2)-alkylthymidines induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), we have replicated a plasmid containing O(2)-methylthymidine (O(2)-Me-dT) or O(2)-[4-(3-pyridyl-4-oxobut-1-yl]thymidine (O(2)-POB-dT) in Escherichia coli w...
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更新日期:1993-03-01 00:00:00
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更新日期:1995-03-01 00:00:00
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更新日期:1990-03-01 00:00:00
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更新日期:1990-09-01 00:00:00
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更新日期:2018-07-16 00:00:00
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abstract::Exposure to the tobacco-related nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine is carcinogenic to humans. Metabolic activation of NNK leads to the formation of DNA adducts, which play a critical role in NNK carcinogenesis. Adducts specific to NNK result from covalent linkag...
journal_title:Chemical research in toxicology
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更新日期:2005-06-01 00:00:00
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更新日期:2009-10-01 00:00:00
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更新日期:2004-02-01 00:00:00