Influence of iron (56Fe2O3 or 54Fe2O3) in the upregulation of cytochrome P4501A1 by benzo[a]pyrene in the respiratory tract of Sprague-Dawley rats.
Any influence of iron in polycyclic aromatic hydrocarbon (PAH)/iron oxide mixtures on the capacity of PAHs to induce metabolizing enzymes will be one of the ways that iron oxides can affect PAH carcinogenicity. Because cytochromes P450 (CYPs) are haemoproteins, it will be of interest to investigate the possible involvement of Fe(2)O(3) in benzo[a]pyrene (BaP)/Fe(2)O(3) mixtures on the induction of CYP1A1 enzymes in the lung. Male Sprague-Dawley rats were instilled intratracheally with haematite ((56)Fe(2)O(3) or (54)Fe(2)O(3), 3 mg), BaP (3 mg) or BaP (3 mg) coated onto haematite ((56)Fe(2)O(3) or (54)Fe(2)O(3)) particles (3 mg). Firstly, mRNA expressions of cyp1a1 were studied. Secondly, protein concentrations and catalytic activities (7-ethoxyresorufin O-deethylase: EROD) of CYP1A1 were determined. Thirdly, (54)Fe from BaP/(54)Fe(2)O(3) mixtures in microsomal proteins was studied using time-of- flight laser microprobe mass spectrometry (ToF-LMMS). Statistically significant increases in mRNA expressions, protein concentrations and catalytic activities of CYP1A1 were observed in animals exposed to BaP, to BaP coated onto (56)Fe(2)O(3) particles or to BaP coated onto (54)Fe(2)O(3) particles versus controls. Both of the BaP/Fe(2)O(3) mixtures induced higher CYP1A1 protein levels and EROD activities than BaP alone. Iron oxide particles per se did not affect mRNA levels of cyp1a1 but only enhanced BaP-mediated increases of CYP1A1 protein levels and activity. The ToF-LMMS spectrum pro fi les showed that the (54)Fe/(56)Fe ratio in the microsomes of BaP coated onto (54)Fe(2)O(3) particle-instilled animals was 1.3 instead of the theoretical ratio (i.e. 0.063) observed in BaP coated onto (56)Fe(2)O(3) particle-instilled animals. Taken together, these novel data support the hypothesis that the Fe(2)O(3)-induced increases of the metabolic activation of BaP might rely on the property of Fe(2)O(3) particles to enhance the BaP-induced translation rate of the cyp1a1 gene into functional haemoproteins.
Garçon
Guillaume
G
Laboratoire de Recherche en Toxicologie Industrielle et Environnementale, Maison de la Recherche en Environnement Industriel de Dunkerque 2, 189A Avenue Maurice Schumann, 59140 Dunkerque, France.
Gosset
Pierre
P
Maunit
Benoît
B
Zerimech
Farid
F
Creusy
Colette
C
Muller
Jean-François
JF
Shirali
Pirouz
P
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005290:Ferric Compounds / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
D005290:Ferric Compounds; C000499:ferric oxide; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1