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Citation
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HERO ID
1254167
Reference Type
Journal Article
Title
Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation
Author(s)
Uno, S; Dalton, TP; Derkenne, S; Curran, CP; Miller, ML; Shertzer, HG; Nebert, DW
Year
2004
Is Peer Reviewed?
1
Journal
Molecular Pharmacology
ISSN:
0026-895X
EISSN:
1521-0111
Volume
65
Issue
5
Page Numbers
1225-1237
Language
English
PMID
15102951
DOI
10.1124/mol.65.5.1225
Web of Science Id
WOS:000220951600020
URL
https://www.proquest.com/docview/71852001?accountid=171501&bdid=13857&_bd=aTFRr6PvrcXyQU793YwM0PXFkSM%3D
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Abstract
The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
Tags
IRIS
•
Benzo(a)pyrene (BaP)
Considered
Cited
Toxicokinetics
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