Cytochrome P450 2a of nasal epithelium: Regulation and role in carcinogen metabolism

Béréziat, Jean-Claude, Raffalli, Francoise, Schmezer, Peter, Frei, Eva, Geneste, Olivier and Lang, Matti A. (1995) Cytochrome P450 2a of nasal epithelium: Regulation and role in carcinogen metabolism. Molecular Carcinogenesis, 14 2: 130-139.


Author Béréziat, Jean-Claude
Raffalli, Francoise
Schmezer, Peter
Frei, Eva
Geneste, Olivier
Lang, Matti A.
Title Cytochrome P450 2a of nasal epithelium: Regulation and role in carcinogen metabolism
Journal name Molecular Carcinogenesis
Publication date 1995-10
Sub-type Article
DOI 10.1002/mc.2940140209
Volume number 14
Issue number 2
ISSN 0899-1987; 1098-2744
Start page 130
End page 139
Total pages 10
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract In this study, we found that rat nasal coumarin-7–hydroxylase (a) activity was two orders of magnitude higher than rat hepatic COH activity and could be induced by adding coumarin to the rats' drinking water. In western blot analysis, an anti-cytochrome P450 (a) 2a-5 (mouse liver COH) antibody recognized a sharp band in the microsomal fraction of rat nasal epithelium but not of the liver; the band comigrated with Cyp2a-5. The intensity of the band was increased by the coumarin treatment. Similarly, in northern blot analysis, a cDNA probe specific for Cyp2a-5 recognized an mRNA in the nasal epithelium having the same size as mouse liver Cyp2a-5 mRNA; however, no hybridizable mRNA was recognized in liver preparations. Unlike the protein level, the level of the mRNA was not increased by coumarin. When northern blot analyses were performed with two oligoprobes specific for rat lung CYP2A3, an mRNA of similar size to Cyp2a-5 mRNA was recognized. In immunoinhibition analysis, anti-Cyp2a-5 antibody inhibited rat nasal COH activity and aflatoxin B1 (AFB1) metabolism completely. It inhibited N-nitrosodiethylamine (a) and 4- (a) -1-(3-pyridyl)-1-butanone (a) metabolism by 80–90%. In contrast, the hepatic metabolism of the four compounds was not affected by the antibody. When coumarin instead of anti-Cyp2a-5 antibody was used, a strong but variable inhibition of the nasal metabolism of AFB1, NDEA, and NNK was seen. The results suggest that an enzyme or enzymes similar to mouse liver Cyp2a-5, one of which may be CYP2A3, is expressed at high levels in rat nasal epithelium but not in the liver and that its expression is increased by coumarin, an odorant and a substrate of Cyp2a-5. The increase probably occurs by protein stabilization or stimulation of translation. The results also show that the enzyme has a key role in the nasal metabolism of three well-known carcinogens, AFB1, NDEA, and NNK and may therefore be an important contributing factor in nasal carcinogenesis.
Keyword Nitrosamines
Aflatoxin B-1
Metabolism
Cyp2a-5
Regulation
Nasal Epithelium
Rat
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article
Collection: National Research Centre for Environmental Toxicology Publications
 
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