Ballmaier Daniel, Epe Bernd
Institute of Pharmacy, University of Mainz, D-55099 Mainz, Germany.
Toxicology. 2006 Apr 17;221(2-3):166-71. doi: 10.1016/j.tox.2006.01.009. Epub 2006 Feb 21.
Exposure of mammalian cells to bromate (BrO3-) generates oxidative DNA modifications, in particular 7,8-dihydro-8-oxo-guanine (8-oxoG). The damaging mechanism is quite unique, since glutathione, which is protective against most oxidants and alkylating agents, mediates a metabolic activation, while bromate itself does not react directly with DNA. Neither enzymes nor transition metals are required as catalysts in the activation. The ultimate DNA damaging species has not yet been established, but experiments under cell-free conditions suggest that neither molecular bromine nor reactive oxygen species such as superoxide, hydrogen peroxide or singlet oxygen are involved. Rather bromine radicals (Br*) or oxides (BrO*, BrO2*) might be responsible. Compared to hypochlorite (ClO-), bromate is much less cytotoxic, probably because the former halite efficiently reacts with proteins and other vitally important cellular constituents. In consequence, oxidative DNA damage and the induction of mutations and micronuclei is easily detectable at non-cytotoxic concentrations of bromate, while DNA damage by hypochlorite is observed only at cytotoxic concentrations and follows a non-linear (hockey-stick-like) dose response.
哺乳动物细胞暴露于溴酸盐（BrO3-）会产生氧化性DNA修饰，特别是7,8-二氢-8-氧代鸟嘌呤（8-oxoG）。其损伤机制颇为独特，因为对大多数氧化剂和烷基化剂具有保护作用的谷胱甘肽介导了一种代谢活化作用，而溴酸盐本身并不直接与DNA反应。活化过程中既不需要酶也不需要过渡金属作为催化剂。最终导致DNA损伤的物质尚未确定，但无细胞条件下的实验表明，分子溴以及超氧化物、过氧化氢或单线态氧等活性氧物种均未参与其中。相反，溴自由基（Br*）或氧化物（BrO*、BrO2*）可能是造成损伤的原因。与次氯酸盐（ClO-）相比，溴酸盐的细胞毒性要小得多，这可能是因为前者能有效地与蛋白质和其他至关重要的细胞成分发生反应。因此，在溴酸盐的非细胞毒性浓度下，氧化性DNA损伤以及突变和微核的诱导很容易被检测到，而次氯酸盐造成的DNA损伤只有在细胞毒性浓度下才能观察到，并且呈现非线性（类似曲棍球棒状）剂量反应。
