DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.
DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.
复制标题
DOI：
10.1289/ehp.93101s535
复制
发表时间：
1993-12
影响因子：
10.4
通讯作者：
Gold LS
中科院分区：
文献类型：
--
作者：
Ames BN;Shigenaga MK;Gold LS
当细胞分裂时，逃避修复的DNA损伤有一定的可能性引起突变。内源性DNA损伤高：每个大鼠细胞存在10(6)个氧化损伤。外源性诱变剂使病变的增加超过内源性病变的背景率。特定病变的有效性取决于它是否被DNA修复系统切除，以及它在细胞分裂时引起突变的可能性。当细胞分裂时，未修复的DNA损伤有一定几率引起突变。因此，外源性药物致突变效应的一个重要因素，无论它是遗传毒性的还是非遗传毒性的，都是它在癌症中最重要的细胞（干细胞）中引起的细胞分裂率（有丝分裂）的增加，干细胞不会被丢弃。增加它们的细胞分裂率会增加突变，从而增加癌症。不分裂的细胞很少致癌。内源性细胞分裂率可能受到激素水平的影响，可能因热量限制而降低，也可能因高剂量的化学物质而增加。如果DNA损伤和细胞分裂的速度都增加了，那么就会对突变（和癌变）产生倍增效应，例如，高剂量的诱变剂也会通过杀死细胞来增加有丝分裂的发生。防御反应性亲电诱变剂（如谷胱甘肽转移酶）的防御系统也几乎都是诱导和缓冲细胞，以抵抗可能导致DNA损伤的活性化学物质的增加。各种DNA修复防御系统，几乎都是诱导的，缓冲细胞免受DNA损伤的任何增加。因此，一种特定化学物质的影响取决于每一种防御的水平，而这又取决于过去的接触历史。外源性药物可以影响这些防御的诱导和有效性。由于饮食中缺乏特定的微量营养素（如抗氧化剂），防御能力可能会部分丧失。
DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10(6) oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).