Kyrtopoulos S A
Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens 11635, Greece.
Mutat Res. 1998 Sep 20;405(2):135-43. doi: 10.1016/s0027-5107(98)00130-4.
Human exposure to methylating agents appears to be widespread, as indicated by the frequent occurrence of methylated DNA adducts in human DNA. The high incidence of methylated DNA adducts even in humans thought not to have suffered extensive exposure to environmental methylating agents implies that chemicals of endogenous origin, probably N-nitroso compounds such as the strongly carcinogenic N-nitrosodimethylamine (NDMA), may be primarily responsible for their formation and raises the question of the carcinogenic risks associated with such exposure. In addition to accumulation of DNA damage, other factors (such as induced cell proliferation) appear to be important in determining the probability of induction of mutation or cancer by NDMA, implying that high to low dose risk extrapolations should not be based on the assumption of dose- or even adduct-linearity. Comparative studies of the accumulation and repair of methylated adducts in humans and animals treated with methylating cytostatic drugs do not reveal significant species differences. Based on this and the dosimetry of adduct accumulation in rats chronically exposed to very low doses of NDMA, it is suggested that the exposure needed to account for the levels of adducts found in human DNA may be of the order of hundreds of micrograms NDMA (or equivalent) per day, a level of exposure which may well represent a significant carcinogenic hazard for man.
人类接触甲基化剂的情况似乎很普遍，人类DNA中甲基化DNA加合物的频繁出现就表明了这一点。即使在那些被认为没有广泛接触环境甲基化剂的人群中，甲基化DNA加合物的高发生率也意味着内源性化学物质，可能是N-亚硝基化合物，如强致癌性的N-亚硝基二甲胺（NDMA），可能是其形成的主要原因，并引发了与这种接触相关的致癌风险问题。除了DNA损伤的积累外，其他因素（如诱导细胞增殖）似乎在决定NDMA诱导突变或癌症的可能性方面也很重要，这意味着高剂量到低剂量的风险推断不应基于剂量甚至加合物线性的假设。对用甲基化细胞抑制药物治疗的人和动物体内甲基化加合物的积累和修复进行的比较研究并未发现显著的物种差异。基于此以及长期暴露于极低剂量NDMA的大鼠体内加合物积累的剂量测定，有人提出，要解释在人类DNA中发现的加合物水平所需的暴露量可能约为每天数百微克NDMA（或等效物），这样的暴露水平很可能对人类构成重大致癌风险。
