Traoré A, Ruiz S, Baudrimont I, Sanni A, Dano S D, Guarigues P, Narbonne J F, Creppy E E
Department of Toxicology, University Victor Segalen Bordeaux 2, France.
Arch Toxicol. 2000 Apr;74(2):79-84. doi: 10.1007/s002040050656.
Okadaic acid (OA) is a marine toxin, a tumour promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Cadmium (Cd) is known to be carcinogenic in animals and humans (group 1 according to the International Agency for Research on Cancer (IARC) classification). Cd also induces oxidative stress in living organisms. Since they are sometimes found simultaneously in mussels, we have evaluated in the present investigation, the lipid peroxidation, as malondialdehyde (MDA) production, in the variation of the ratios of 8-(OH)-dG/10(5)dG and m5dC/(dC + m5dC) induced by OA and/or Cd in Caco-2 cells. When cells were treated exclusively by OA (15 ng/ml) or Cd (0.625 and 5 microg/ml) for 24 h, protein synthesis was inhibited (by 42 +/- 5%, 18 +/- 13%, and 90 +/- 4% respectively) while MDA production was 2,235 +/- 129, 1710 +/- 20, and 11,496 +/-1,624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m(5)dC/(m(5)dC + dC) was increased from 3 +/- 0.15 to 9 +/- 0.15 and the ratio 8-(OH)-dG/10(5) dG also (from 36 +/- 2 to 76 +/- 6). The combination of OA and Cd also increased the level of MDA (1,6874 +/- 2,189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.
冈田酸（OA）是一种海洋毒素、肿瘤促进剂和细胞凋亡诱导剂。它主要抑制蛋白磷酸酶、蛋白质合成并增强脂质过氧化作用。已知镉（Cd）对动物和人类具有致癌性（根据国际癌症研究机构（IARC）分类属于1类致癌物）。镉还会在生物体内诱导氧化应激。由于它们有时会在贻贝中同时被发现，因此在本研究中，我们评估了在Caco-2细胞中，由OA和/或Cd诱导的脂质过氧化（以丙二醛（MDA）生成量衡量）、8-（羟基）-脱氧鸟苷/10⁵脱氧鸟苷（8-(OH)-dG/10(5)dG）和5-甲基胞嘧啶/（胞嘧啶 + 5-甲基胞嘧啶）（m5dC/(dC + m5dC)）比值的变化情况。当细胞仅用OA（15纳克/毫升）或Cd（0.625和5微克/毫升）处理24小时时，蛋白质合成受到抑制（分别抑制42±5%、18±13%和90±4%），而MDA生成量分别为2235±129、1710±20和11496±1624皮摩尔/毫克蛋白质。此外，每种毒物都会诱导DNA中碱基的修饰；氧化碱基和甲基化胞嘧啶增加。OA和镉的组合具有更强的细胞毒性，并导致更多的DNA碱基修饰；5-甲基胞嘧啶/（5-甲基胞嘧啶 + 胞嘧啶）（m(5)dC/(m(5)dC + dC)）比值从3±0.15增加到9±0.15，8-（羟基）-脱氧鸟苷/10⁵脱氧鸟苷（8-(OH)-dG/10(5) dG）比值也从36±2增加到76±6。OA和Cd的组合还增加了MDA水平（16874±2189皮摩尔/毫克蛋白质）。目前的结果强烈表明，这两种毒物诱导的氧化应激导致的DNA损伤可能通过表观遗传过程显著增加它们的致癌性。
