Grant S G, Zhang Y P, Klopman G, Rosenkranz H S
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15238, USA. sgg+@pitt.edu
Mutat Res. 2000 Feb 16;465(1-2):201-29. doi: 10.1016/s1383-5718(99)00186-2.
An SAR model of the induction of mutations at the tk(+/-) locus of L5178Y mouse lymphoma cells (MLA, for mouse lymphoma assay) was derived based upon a re-evaluation of experimental results reported by a Gene-Tox (GT) working group [A.D. Mitchell, A.E. Auletta, D. Clive, P.E. Kirby, M.M. Moore, B.C. Myhr, The L5178Y/tk(+/-) mouse lymphoma specific gene and chromosomal mutation assay. A phase III report of the U.S. Environmental Protection Agency Gene-Tox Program, Mutation Res. 394 (1997) 177-303.]. The predictive performance of the GT MLA SAR model was similar to that of a Salmonella mutagenicity model containing the same number of chemicals. However, the structural determinants (biophores) derived from the GT MLA SAR model include both electrophilic as well as non-electrophilic moieties, suggesting that the induction of mutations in the MLA may occur by both direct interaction with DNA and by non-DNA-related mechanisms. This was confirmed by the observation that the set of biophores associated with MLA overlapped significantly with those associated with phenomena related to loss of heterozygosity, chromosomal rearrangements and aneuploidy. The MLA SAR model derived from the GT data evaluation was significantly more predictive than an SAR model previously derived from MLA data reported by the US National Toxicology Program [B. Henry, S.G. Grant, G. Klopman, H.S. Rosenkranz, Induction of forward mutations at the thymidine kinase locus of mouse lymphoma cells: evidence for electrophilic and non-electrophilic mechanisms, Mutation Res. 397 (1998) 331-335.]. Moreover, the latter model appeared to be more complex than the former, suggesting that the GT induction data was both simpler mechanistically and more homogeneous than that of the NTP.
基于对基因毒理学（GT）工作组报告的实验结果的重新评估，得出了L5178Y小鼠淋巴瘤细胞tk(+/-)位点诱导突变的结构活性关系（SAR）模型（用于小鼠淋巴瘤试验的MLA）[A.D. 米切尔、A.E. 奥列塔、D. 克莱夫、P.E. 柯比、M.M. 摩尔、B.C. 迈尔，L5178Y/tk(+/-)小鼠淋巴瘤特异性基因和染色体突变试验。美国环境保护局基因毒理学计划的III期报告，《突变研究》394（1997）177 - 303]。GT MLA SAR模型的预测性能与包含相同数量化学物质的沙门氏菌诱变性模型相似。然而，从GT MLA SAR模型得出的结构决定因素（生物基团）包括亲电和亲非亲电部分，这表明MLA中突变的诱导可能通过与DNA的直接相互作用以及非DNA相关机制发生。这一点通过观察得到证实，即与MLA相关的生物基团集与与杂合性丧失、染色体重排和非整倍体相关现象的生物基团集有显著重叠。从GT数据评估得出的MLA SAR模型比之前从美国国家毒理学计划报告的MLA数据得出的SAR模型预测性更强[B. 亨利、S.G. 格兰特、G. 克洛普曼、H.S. 罗森克兰茨，小鼠淋巴瘤细胞胸苷激酶位点正向突变的诱导：亲电和亲非亲电机制的证据，《突变研究》397（1998）331 - 335]。此外，后一个模型似乎比前一个更复杂，这表明GT诱导数据在机制上更简单且比NTP的数据更具同质性。
