Ho I C, Yih L H, Kao C Y, Lee T C
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Mutat Res. 2000 Jul 20;452(1):41-50. doi: 10.1016/s0027-5107(00)00035-x.
Numerous reports have shown that oxidative stress is involved in arsenite-induced genetic damage. Arsenite is also a potent inducer of heme oxygenase (HO)-1. To understand whether HO-1 could function as a cellular antioxidant and protect cells from arsenite injury, the effects of tin-protoporphyrin (SnPP), a competitive inhibitor of HO-1, on arsenite-induced genetic damage were examined in human skin fibroblasts (HFW). In the present study, we found that SnPP at 100 microM significantly potentiated arsenite-induced cytotoxicity, DNA strand breaks (assayed by alkaline single cell gel electrophoresis(SCGE)), and chromatid breaks. Although arsenite alone mainly induced kinetochore-plus micronuclei (K(+)-MN), SnPP only synergistically enhanced kinetochore-negative micronuclei (K(-)-MN). The increase in K(-)-MN by SnPP cotreatment was consistent with the increase in DNA strand breaks and chromatid breaks caused by SnPP. However, at higher arsenite doses, K(+)-MN was significantly reduced by SnPP. Pretreatment of HFW cells with hemin, an inducer of HO-1, significantly attenuated the cytotoxicity of arsenite. Therefore, the present results suggest that HO-1 induction by arsenite plays certain roles in protecting cells from arsenite-induced injury.
大量报告表明，氧化应激参与了亚砷酸盐诱导的遗传损伤。亚砷酸盐也是血红素加氧酶（HO）-1的强效诱导剂。为了了解HO-1是否可作为细胞抗氧化剂发挥作用并保护细胞免受亚砷酸盐损伤，我们在人皮肤成纤维细胞（HFW）中检测了HO-1的竞争性抑制剂锡原卟啉（SnPP）对亚砷酸盐诱导的遗传损伤的影响。在本研究中，我们发现100微摩尔的SnPP显著增强了亚砷酸盐诱导的细胞毒性、DNA链断裂（通过碱性单细胞凝胶电泳（SCGE）检测）和染色单体断裂。虽然单独的亚砷酸盐主要诱导动粒加微核（K(+)-MN），但SnPP仅协同增强动粒阴性微核（K(-)-MN）。SnPP共处理导致的K(-)-MN增加与SnPP引起的DNA链断裂和染色单体断裂增加一致。然而，在较高的亚砷酸盐剂量下，SnPP显著降低了K(+)-MN。用HO-1诱导剂血红素预处理HFW细胞可显著减弱亚砷酸盐的细胞毒性。因此，本研究结果表明，亚砷酸盐诱导的HO-1在保护细胞免受亚砷酸盐诱导的损伤中发挥了一定作用。
