Bakale G, McCreary R D
Case Western Reserve University, Department of Radiology, Cleveland, OH 44106-5000.
Carcinogenesis. 1992 Aug;13(8):1437-45. doi: 10.1093/carcin/13.8.1437.
A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.
采用一种物理化学致癌物筛选试验来测量105种化学物质的电子附着速率常数kes,这些化学物质已由美国国立癌症研究所/国家毒理学计划(NCI/NTP)在长期啮齿动物生物测定和短期体外试验中进行了筛选。在kes试验中,采用脉冲电导率技术来产生并监测过量电子的衰减,这些过量电子作为啮齿动物靶组织的亲核替代物。在已被发现既是啮齿动物致癌物又是沙门氏菌诱变剂的61种化学物质中,有36种的kes等于或大于四氯化碳的扩散控制kes,被认为是kes试验阳性反应。相比之下,其余44种假定的非致癌物和非诱变剂中的29种产生的kes是kes试验阴性反应。这些结果与之前报道的46种非诱变致癌物和20种诱变非致癌物的kes反应相结合,并进行评估,以确定kes所提供的电子接受能力测量在多大程度上补充或重叠了化学物质的亲电性或DNA反应性,这由艾姆斯沙门氏菌试验菌株中的阳性诱变反应或化学物质的阳性结构警示(S/As)所表明。综合的kes试验结果表明,kes试验在识别啮齿动物致癌物方面的总体预测能力与艾姆斯沙门氏菌试验和S/As相当,并互为补充。此外,电子作为遗传毒性和非遗传毒性电子接受分子的非特异性亲核靶标,似乎以相同效率附着于在啮齿动物各种组织中具有活性的致癌物。过量电子的这一特性表明,通过将测得的kes与适当的亲脂性或药代动力学参数相结合,可以提高kes试验的预测能力。根据电子供体/受体化学的最新进展以及结构 - 活性关系在识别致癌物中的应用,讨论了在致癌物与靶组织之间的化学相互作用之前曾被提出的一个化学前电子转移步骤。