Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu, Mie 514-8507, Japan.
Chem Res Toxicol. 2013 Oct 21;26(10):1455-63. doi: 10.1021/tx400182n. Epub 2013 Sep 25.
Drinking alcohol is a risk factor for breast cancer. Salsolinol (SAL) is endogenously formed by a condensation reaction of dopamine with acetaldehyde, a major ethanol metabolite, and SAL is detected in blood and urine after alcohol intake. We investigated the possibility that SAL can participate in tumor initiation and promotion by causing DNA damage and cell proliferation, leading to alcohol-associated mammary carcinogenesis. SAL caused oxidative DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), in the presence of transition metal ions, such as Cu(II) and Fe(III)EDTA. Inhibitory effects of scavengers on SAL-induced DNA damage and the electron spin resonance study indicated the involvement of H₂O₂, which is generated via the SAL radical. Experiments on scavengers and site specificity of DNA damage suggested ·OH generation via a Fenton reaction and copper-peroxide complexes in the presence of Fe(III)EDTA and Cu(II), respectively. SAL significantly increased 8-oxodG formation in normal mammary epithelial MCF-10A cells. In addition, SAL induced cell proliferation in estrogen receptor (ER)-negative MCF-10A cells, and the proliferation was inhibited by an antioxidant N-acetylcysteine and an epidermal growth factor receptor (EGFR) inhibitor AG1478, suggesting that reactive oxygen species may participate in the proliferation of MCF-10A cells via EGFR activation. Furthermore, SAL induced proliferation in estrogen-sensitive breast cancer MCF-7 cells, and a surface plasmon resonance sensor revealed that SAL significantly increased the binding activity of ERα to the estrogen response element but not ERβ. In conclusion, SAL-induced DNA damage and cell proliferation may play a role in tumor initiation and promotion of multistage mammary carcinogenesis in relation to drinking alcohol.
饮酒是乳腺癌的一个风险因素。Salsolinol（SAL）是由多巴胺与乙醛缩合反应内源性形成的，乙醛是乙醇的主要代谢物，饮酒后可在血液和尿液中检测到 SAL。我们研究了 SAL 通过引起 DNA 损伤和细胞增殖从而参与肿瘤起始和促进的可能性，导致与酒精相关的乳腺致癌作用。SAL 在过渡金属离子（如 Cu(II) 和 Fe(III)EDTA）存在下引起氧化 DNA 损伤，包括 8-氧代-7,8-二氢-2'-脱氧鸟苷（8-oxodG）。清除剂对 SAL 诱导的 DNA 损伤的抑制作用和电子自旋共振研究表明，H₂O₂的参与，H₂O₂是通过 SAL 自由基生成的。清除剂实验和 DNA 损伤的位点特异性表明，在 Fe(III)EDTA 和 Cu(II)存在下，通过 Fenton 反应和铜过氧化物复合物分别生成·OH。SAL 显著增加了正常乳腺上皮 MCF-10A 细胞中 8-oxodG 的形成。此外，SAL 诱导雌激素受体（ER）阴性 MCF-10A 细胞增殖，抗氧化剂 N-乙酰半胱氨酸和表皮生长因子受体（EGFR）抑制剂 AG1478 抑制增殖，表明活性氧可能通过 EGFR 激活参与 MCF-10A 细胞的增殖。此外，SAL 诱导雌激素敏感的乳腺癌 MCF-7 细胞增殖，表面等离子体共振传感器显示 SAL 显著增加了 ERα 与雌激素反应元件的结合活性，但不增加 ERβ。总之，SAL 诱导的 DNA 损伤和细胞增殖可能在与饮酒有关的多阶段乳腺致癌作用的肿瘤起始和促进中发挥作用。
