Becker Andrea, Albrecht Catrin, Knaapen Ad M, Schins Roel P F, Höhr Doris, Ledermann Kirstin, Borm Paul J A
Particle Research, Institut für Umweltmedizinische Forschung gGmbH an der Heinrich-Heine Universität, Dusseldorf, Germany.
Arch Toxicol. 2006 May;80(5):258-68. doi: 10.1007/s00204-006-0084-2. Epub 2006 Mar 18.
Respirable quartz has been classified as a human lung carcinogen, but the mechanism by which quartz exposure leads to lung cancer has not been clarified. Consistently higher risks of lung cancer are reported in smokers with quartz exposure and we therefore hypothesised that quartz exposure may alter the expression of enzyme systems involved in activation/detoxification of pre-carcinogens in cigarette smoke. More specifically we studied cytochrome P4501A1 (CYP1A1) expression using reverse transcriptase polymerase chain reaction and immunohistochemistry (IHC) upon in vitro and in vivo quartz exposure. In vitro incubation of rat lung epithelial cells with DQ12 quartz for 24 h showed a dose-dependent induction of CYP1A1-mRNA. On the other hand, CYP1A1 message was not increased in lung epithelial cells isolated from rats at 3, 28 or 90 days after intratracheal instillation of 2 mg DQ12. Following IHC for CYP1A1 protein in rat lung sections from later time-points (180 and 360 days), we observed an increase in the number of CYP1A1 positive cells. After in vivo quartz exposure, protein expression of the Aryl hydrocarbon receptor (AhR) was increased and nuclear translocation of AhR was observed at the same time-points. In conclusion, our findings demonstrate an effect of quartz exposure on chronic CYP1A1 expression in vivo, whereas the in vitro models show an immediate upregulation. We suggest that this upregulation of CYP1A1 may act as a co-carcinogenic pathway in quartz exposed workers by activation of pre-carcinogens such as those present in cigarette smoke.
可吸入性石英已被列为人类肺癌致癌物，但石英暴露导致肺癌的机制尚未阐明。据报道，接触石英的吸烟者患肺癌的风险持续较高，因此我们推测，石英暴露可能会改变参与香烟烟雾中致癌物前体激活/解毒的酶系统的表达。更具体地说，我们在体外和体内石英暴露后，使用逆转录聚合酶链反应和免疫组织化学（IHC）研究了细胞色素P4501A1（CYP1A1）的表达。用DQ12石英对大鼠肺上皮细胞进行24小时的体外培养显示，CYP1A1-mRNA呈剂量依赖性诱导。另一方面，在气管内注入2mg DQ12后3天、28天或90天，从大鼠分离的肺上皮细胞中CYP1A1的信息没有增加。在对后期时间点（180天和360天）的大鼠肺切片进行CYP1A1蛋白的免疫组织化学检测后，我们观察到CYP1A1阳性细胞数量增加。在体内石英暴露后，芳烃受体（AhR）的蛋白表达增加，并且在同一时间点观察到AhR的核转位。总之，我们的研究结果表明石英暴露对体内慢性CYP1A1表达有影响，而体外模型显示出立即上调。我们认为，CYP1A1的这种上调可能通过激活香烟烟雾中存在的致癌物前体等物质，在接触石英的工人中作为一种协同致癌途径。
