Garçon Guillaume, Gosset Pierre, Maunit Benoît, Zerimech Farid, Creusy Colette, Muller Jean-François, Shirali Pirouz
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.
J Appl Toxicol. 2004 May-Jun;24(3):249-56. doi: 10.1002/jat.979.
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.
多环芳烃（PAH）/氧化铁混合物中的铁对PAHs诱导代谢酶能力的任何影响，都将是氧化铁影响PAH致癌性的途径之一。由于细胞色素P450（CYPs）是血红素蛋白，因此研究Fe(2)O(3)在苯并[a]芘（BaP）/Fe(2)O(3)混合物中对肺中CYP1A1酶诱导的可能作用将很有意义。将赤铁矿（(56)Fe(2)O(3)或(54)Fe(2)O(3)，3mg）、BaP（3mg）或包被在赤铁矿（(56)Fe(2)O(3)或(54)Fe(2)O(3)）颗粒（3mg）上的BaP（3mg）经气管内滴注到雄性Sprague-Dawley大鼠体内。首先，研究cyp1a1的mRNA表达。其次，测定CYP1A1的蛋白质浓度和催化活性（7-乙氧基异吩唑酮O-脱乙基酶：EROD）。第三，使用飞行时间激光微探针质谱仪（ToF-LMMS）研究微粒体蛋白中BaP/(54)Fe(2)O(3)混合物中的(54)Fe。与对照组相比，在暴露于BaP、包被在(56)Fe(2)O(3)颗粒上的BaP或包被在(54)Fe(2)O(3)颗粒上的BaP的动物中，观察到CYP1A1的mRNA表达、蛋白质浓度和催化活性有统计学意义的增加。两种BaP/Fe(2)O(3)混合物诱导的CYP1A1蛋白水平和EROD活性均高于单独的BaP。氧化铁颗粒本身不影响cyp1a1的mRNA水平，仅增强BaP介导的CYP1A1蛋白水平和活性的增加。ToF-LMMS光谱图谱显示，经气管内滴注包被有(54)Fe(2)O(3)颗粒的BaP的动物微粒体中的(54)Fe/(56)Fe比率为1.3，而不是经气管内滴注包被有(56)Fe(2)O(3)颗粒的BaP的动物中观察到的理论比率（即,0.063）。综上所述，这些新数据支持以下假设：Fe(2)O(3)诱导的BaP代谢活化增加可能依赖于Fe(2)O(3)颗粒增强BaP诱导的cyp1a1基因向功能性血红素蛋白的翻译速率的特性。
