Korashy Hesham M, El-Kadi Ayman O S
Faculty of Pharmacy and Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, AB, Canada T6G 2N8.
Toxicol In Vitro. 2008 Feb;22(1):154-8. doi: 10.1016/j.tiv.2007.08.003. Epub 2007 Aug 17.
Co-contamination with complex mixtures of heavy metals and polycyclic aromatic hydrocarbons (PAHs) is a common environmental problem with multiple biological consequences. In this study, we tested in human hepatoma HepG2 cells the potential effects of three prominent environmental heavy metals, mercury (Hg(2+)), lead (Pb(2+)), and copper (Cu(2+)), on the induction of cytochrome P450 1A1 (CYP1A1) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent PAH. Our results show that TCDD in the absence and presence of heavy metals did not significantly affect HepG2 cell viability using MTT and LDH leakage assays. Exposure of HepG2 cells with either Hg(2+) or Pb(2+) significantly decreased, whereas Cu(2+) potentiated the CYP1A1 induction mediated by TCDD at the activity levels. In a manner similar to CYP1A1 activity, both Hg(2+) and Pb(2+) significantly down-regulated, while Cu(2+) up-regulated, the induction of CYP1A1 protein mediated by TCDD, suggesting that the modulations of CYP1A1 by heavy metals are mediated at least in part at the translational level. Based on these results, exposure to metal/PAH mixtures would differentially modulate PAHs-mediated carcinogenicity.
重金属与多环芳烃（PAHs）的复杂混合物共同污染是一个常见的环境问题，会产生多种生物学后果。在本研究中，我们在人肝癌HepG2细胞中测试了三种主要环境重金属汞（Hg(2+)）、铅（Pb(2+)）和铜（Cu(2+)）对最有效的PAH——2,3,7,8-四氯二苯并对二恶英（TCDD）诱导细胞色素P450 1A1（CYP1A1）的潜在影响。我们的结果表明，使用MTT和LDH泄漏试验，在不存在和存在重金属的情况下，TCDD对HepG2细胞活力均无显著影响。用Hg(2+)或Pb(2+)处理HepG2细胞会显著降低TCDD介导的CYP1A1诱导活性，而Cu(2+)则增强该诱导活性。与CYP1A1活性类似，Hg(2+)和Pb(2+)均显著下调TCDD介导的CYP1A1蛋白诱导，而Cu(2+)则上调该诱导，这表明重金属对CYP1A1的调节至少部分是在翻译水平介导的。基于这些结果，暴露于金属/PAH混合物会对PAHs介导的致癌性产生不同的调节作用。
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