Garçon Guillaume, Gosset Pierre, Zerimech Farid, Grave-Descampiaux Béatrice, Shirali Pirouz
Laboratoire de Recherche en Toxicologie Industrielle et Environnementale, Université du Littoral-Côte d'Opale 220, Avenue de l'Université, BP 5526, 59379 Dunkerque Cedex 1, France.
Toxicol Lett. 2004 Apr 21;150(2):179-89. doi: 10.1016/j.toxlet.2004.01.005.
In this work, the question that needs to be answered was whether concurrent exposure to iron oxides and polycyclic aromatic hydrocarbons (PAHs) could affect the induction of PAH-metabolizing enzymes. Male Sprague-Dawley rats were intratracheally instilled with hematite (Fe(2)O(3); 3mg), benzo(a)pyrene (B(a)P; 3mg), or B(a)P (3mg)-coated onto Fe(2)O(3) particles (3mg). Forty-eight hours later, we investigated mRNA expressions of cytochrome p4501a1 (cyp1a1), microsomal epoxide hydrolase (meh), and glutathione-S-transferase-ya and -yc (gst-ya and gst-yc, respectively), protein concentrations of CYP1A1, and 7-ethoxyresorufin O-deethylase (EROD) activities in lungs. Exposure to B(a)P alone or coated-onto Fe(2)O(3) particles induced cyp1a1 gene transcription (P < 0.01) and increased both the CYP1A1 protein levels (P < 0.01) and the EROD activities (P < 0.001). However, in this work, we focused our attention on the potential of Fe(2)O(3) in B(a)P/Fe(2)O(3) mixtures to affect the capacity of B(a)P to induce PAH-metabolizing enzymes. Exposure to B(a)P-coated onto Fe(2)O(3) particles increased meh mRNA expressions (1.15-fold, P < 0.05), CYP1A1 protein concentrations (1.85-fold, P < 0.05), and EROD activities (1.95-fold, P < 0.01), versus exposure to B(a)P alone. Hence, animal short-term exposure to B(a)P-coated onto Fe(2)O(3) particles favored dramatically the induction of PAH-bioactivating enzymes to the detriment of PAH-inactivating enzymes in lungs. Taken together, these results support the hypothesis that the Fe(2)O(3)-induced increase of the metabolic activation of B(a)P might rely on several properties of Fe(2)O(3), including its capacity to enhance the rate of CYP1A1 hemoprotein elaboration. The influence of Fe(2)O(3) in B(a)P/Fe(2)O(3) mixtures on the ability of B(a)P to induce PAH-metabolizing enzymes will also be one of the fundamental ways that Fe(2)O(3) can affect B(a)P carcinogenicity in lungs.
在本研究中，需要回答的问题是，同时暴露于氧化铁和多环芳烃（PAHs）是否会影响PAH代谢酶的诱导。将赤铁矿（Fe₂O₃；3mg）、苯并(a)芘（B(a)P；3mg）或涂覆在Fe₂O₃颗粒（3mg）上的B(a)P（3mg）经气管内注入雄性Sprague-Dawley大鼠体内。48小时后，我们研究了肺组织中细胞色素p4501a1（cyp1a1）、微粒体环氧化物水解酶（meh）、谷胱甘肽-S-转移酶-ya和-yc（分别为gst-ya和gst-yc）的mRNA表达、CYP1A1蛋白浓度以及7-乙氧基异吩唑酮O-脱乙基酶（EROD）活性。单独暴露于B(a)P或暴露于涂覆在Fe₂O₃颗粒上的B(a)P均可诱导cyp1a1基因转录（P < 0.01），并使CYP1A1蛋白水平（P < 0.01）和EROD活性增加（P < 0.001）。然而，在本研究中，我们关注的是Fe₂O₃在B(a)P/Fe₂O₃混合物中影响B(a)P诱导PAH代谢酶能力的可能性。与单独暴露于B(a)P相比，暴露于涂覆在Fe₂O₃颗粒上的B(a)P可使meh mRNA表达增加（1.15倍，P < 0.05）、CYP1A1蛋白浓度增加（1.85倍，P < 0.05）以及EROD活性增加（1.95倍，P < 0.01）。因此，动物短期暴露于涂覆在Fe₂O₃颗粒上的B(a)P显著有利于肺组织中PAH生物激活酶的诱导，而不利于PAH失活酶的诱导。综上所述，这些结果支持以下假设：Fe₂O₃诱导的B(a)P代谢激活增加可能依赖于Fe₂O₃的多种特性，包括其增强CYP1A1血红蛋白合成速率的能力。Fe₂O₃在B(a)P/Fe₂O₃混合物中对B(a)P诱导PAH代谢酶能力的影响也将是Fe₂O₃影响肺组织中B(a)P致癌性的基本途径之一。
