Department of Translational Research NTMS, University of Pisa Medical School, Pisa 56126, Italy.
Université de Lorraine, CITHEFOR, F-54000 Nancy, France.
Toxicol Sci. 2020 Oct 1;177(2):476-482. doi: 10.1093/toxsci/kfz175.
Asbestos is the main causative agent of malignant pleural mesothelioma. The variety known as crocidolite (blue asbestos) owns the highest pathogenic potential, due to the dimensions of its fibers as well as to its content of iron. The latter can in fact react with macrophage-derived hydrogen peroxide in the so called Fenton reaction, giving rise to highly reactive and mutagenic hydroxyl radical. On the other hand, hydroxyl radical can as well originate after thiol-dependent reduction of iron, a process capable of starting its redox cycling. Previous studies showed that glutathione (GSH) is one such thiol, and that cellular gamma-glutamyltransferase (GGT) can efficiently potentiate GSH-dependent iron redox cycling and consequent oxidative stress. As GGT is expressed in macrophages and is released upon their activation, the present study was aimed at verifying the hypothesis that GSH/GGT-dependent redox reactions may participate in the oxidative stress following the activation of macrophages induced by crocidolite asbestos. Experiments in acellular systems confirmed that GGT-mediated metabolism of GSH can potentiate crocidolite-dependent production of superoxide anion, through the production of highly reactive dipeptide thiol cysteinyl-glycine. Cultured THP-1 macrophagic cells, as well as isolated monocytes obtained from healthy donors and differentiated to macrophages in vitro, were investigated as to their expression of GGT and the effects of exposure to crocidolite. The results show that crocidolite asbestos at subtoxic concentrations (50-250 ng/1000 cells) can upregulate GGT expression, which raises the possibility that macrophage-initiated, GSH/GGT-dependent pro-oxidant reactions may participate in the pathogenesis of tissue damage and inflammation consequent to crocidolite intoxication.
石棉是恶性胸膜间皮瘤的主要致病因素。已知的青石棉（蓝石棉）品种具有最高的致病潜能，这归因于其纤维的尺寸以及其铁含量。铁实际上可以与巨噬细胞衍生的过氧化氢在所谓的芬顿反应中反应，产生高反应性和致突变的羟自由基。另一方面，羟自由基也可以在铁的硫醇依赖性还原后产生，这一过程能够启动其氧化还原循环。先前的研究表明，谷胱甘肽 (GSH) 是一种硫醇，细胞γ-谷氨酰转移酶 (GGT) 可以有效地增强 GSH 依赖性铁的氧化还原循环和随后的氧化应激。由于 GGT 在巨噬细胞中表达，并在其激活时释放，因此本研究旨在验证以下假设：即 GSH/GGT 依赖性氧化还原反应可能参与由青石棉诱导的巨噬细胞激活后的氧化应激。非细胞系统中的实验证实，GGT 介导的 GSH 代谢可以通过产生高反应性二肽硫醇半胱氨酸-甘氨酸来增强青石棉依赖性超氧阴离子的产生。研究了培养的 THP-1 巨噬细胞以及从健康供体获得的分离单核细胞，并在体外分化为巨噬细胞，以研究它们的 GGT 表达以及暴露于青石棉的影响。结果表明，亚毒性浓度（50-250ng/1000 细胞）的青石棉可以上调 GGT 表达，这表明巨噬细胞起始的、GSH/GGT 依赖性的促氧化剂反应可能参与了青石棉中毒引起的组织损伤和炎症的发病机制。
