Mäki-Paakkanen J, Hakulinen P
Department of Environmental Health, National Public Health Institute, PO Box 95, FI-70701 Kuopio, Finland.
Toxicol In Vitro. 2008 Mar;22(2):535-40. doi: 10.1016/j.tiv.2007.10.001. Epub 2007 Oct 9.
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a disinfection by-product in chlorinated drinking water, is a multisite carcinogen in rats. One main target organ is the liver. The mechanism of the tumorigenicity was evaluated by testing the genotoxicity of MX in rat liver epithelial cell line cells. In the studies, the single cell gel/Comet assay and the hypoxanthine phosphoribosyl transferase locus assay to 6-thioguanine resistance were used. MX induced a dose-related genotoxic response in the comet assay. The lowest effective concentration was 120 microM when the exposure was in medium plus supplements and 3.75 microM when the exposure was in phosphate-buffered salt solution. MX also increased the frequency of TG(r) mutants, when the cells were treated in phosphate-buffered salt solution, at a concentration range of 2.3-9.2 microM. The present results show for the first time that MX causes DNA damage and gene mutations in rat liver epithelial cells, the target cells of MX's tumorigenicity in rats. We have earlier shown that MX also inhibits gap junctional intercellular communication in the same cells. The genotoxic effects were induced starting at about 60 times higher concentration, in identical exposure conditions, compared with the lowest concentration of MX causing the tumor promoter effect.
3-氯-4-（二氯甲基）-5-羟基-2（5H）-呋喃酮（MX）是氯化饮用水中的一种消毒副产物，是大鼠体内的一种多部位致癌物。一个主要靶器官是肝脏。通过检测MX对大鼠肝上皮细胞系细胞的遗传毒性来评估其致瘤机制。在这些研究中，使用了单细胞凝胶/彗星试验和次黄嘌呤磷酸核糖转移酶基因座对6-硫鸟嘌呤抗性的试验。MX在彗星试验中诱导了剂量相关的遗传毒性反应。当在培养基加补充剂中暴露时，最低有效浓度为120微摩尔，当在磷酸盐缓冲盐溶液中暴露时为3.75微摩尔。当细胞在磷酸盐缓冲盐溶液中以2.3-9.2微摩尔的浓度范围处理时，MX也增加了TG（r）突变体的频率。目前的结果首次表明，MX在大鼠肝上皮细胞中引起DNA损伤和基因突变，而大鼠肝上皮细胞是MX在大鼠体内致瘤性的靶细胞。我们之前已经表明，MX在相同细胞中也抑制间隙连接细胞间通讯。在相同的暴露条件下，与引起肿瘤促进作用的最低浓度的MX相比，遗传毒性效应在大约高60倍的浓度时开始诱导。
