抗乙肝病毒新药Bay41-4109的发现毒理学研究

目的:利用发现毒理学中的临床前先导化合物优化技术(preclinical lead optimization technolo-gies,PLOTs)对抗乙肝病毒候选新药Bay41-4109的一般毒性、遗传毒性和生殖毒性进行研究,为早期发现候选新药的毒性提供实验依据.方法:一般毒性研究中分别以MTT比色法和上下法检测Bay41-4109的体外细胞毒性和小鼠LD50;遗传毒性研究中分别以Ames波动试验、SOS显色试验、双核细胞微核试验检测Bay41-4109诱发鼠伤寒沙门菌基因回复突变的能力、诱发大肠杆菌的原发DNA损伤效应以及对CHL细胞的染色体断裂效应;生殖毒性研究中以大鼠胚胎中脑细胞微团培养试验来检测Bay41-4109的致畸性.结果:Bay41-4109对CHL细胞的IC50为54.0 μmol·L-1,对雌性小鼠的LD50大于2 000 mg·kg-1.无论有无S9活化,Bay41-4109均不引起沙门菌回复突变,也不导致DNA损伤和染色体断裂.Bay41-4109对大鼠胚胎中脑细胞亦无致畸作用.结论:早期毒性筛选结果表明:Bay41-4109未表现明显的遗传毒性和生殖毒性.     

新药评价中遗传毒性试验方法学研究及其发展趋势

比较各国的新药遗传毒性评价方案 ,重点介绍 Ames试验和微核试验的研究进展、遗传毒性评价的新技术和新方法 (FISH技术、彗星试验等 ) ,并提出了新世纪遗传毒理学的发展趋势。     

盐酸川丁特罗遗传毒性研究

目的：研究盐酸川丁特罗（SPFF）的遗传毒性。方法：采用Ames试验、哺乳动物培养细胞染色体畸变试验、小鼠微核试验，考察SPFF对鼠伤寒沙门菌和细胞的遗传毒性。结果：经Ames试验、CHL细胞染色体畸变试验、小鼠微核试验，SPFF的结果均呈阴性。结论：SPFF无遗传毒性。     

灵芝孢子粉胶囊急性毒性及遗传毒性实验研究

目的：了解灵芝孢子粉胶囊的毒理学，评价其安全性。方法：小鼠急性毒性试验和遗传毒性试验（Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验）。结果与结论：灵芝孢子粉胶囊的小鼠经口LDs。〉10g／kg，在Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验中均呈阴性反应，未显示有遗传毒性作用，表明灵芝孢子粉胶囊基本无毒性。     

FK系列化合物的早期毒性评价

目的FK系列化合物是我所在研的一类新药。可能作用机制是FK506/FK复合物作用于2种钙释放通道ryanodine受体和IP3受体,使钙内流增加;或激活TGF-β1受体,促进神经胶质细胞生长因子的合成。目前尚处于研发的早期阶段,其毒性作用还不清楚。本次研究利用短期毒性筛选方法对其可能毒性进行初步筛选,及早发现和淘汰不适合继续开发的化合物。方法采用MTT比色法观察5种新化学实体对CHL细胞的毒性作用,并利用细胞毒性IC50值对急性毒性LD50值进行预测;上下法检测化学物质对小鼠的急性毒性;Ames波动试验和体外微核试验检测其遗传毒性;利用大鼠胚胎中脑细胞微团培养法,对其致畸性进行预测。结果FK(Z48、3081、308、L04和1205)系列化合物对CHL细胞的半数抑制剂量(IC50)分别为0.67、1.79、1.68、3.04和3.62mg/ml。急性毒性LD50的预测值分别为2087.6、3300.7、3331.8、4904.3和>5000mg/kg。上下法检测5种化合物对小鼠的急性毒性LD50,除Z48为1634.0mg/kg外,其余均大于2000mg/kg。以急性毒性LD50预测值和检测值为基础对化合物进行毒性分级,二者相比,仅Z48分级略有差异,其他4种化合物的毒性分级基本一致。提示体外细胞毒性数据对化学物质的体内急性毒性具有良好的预测性。无论有无S9的代谢活化,5种新化学物质均未显示出遗传毒性和明显的致畸作用。结论短期毒性筛选体系可从不同的毒性终点对新化学实体进行比较和筛选,为候选化合物的选择提供重要的技术体系。5种FK系列化合物毒性均较低,从毒理学角度考虑,均适合做进一步研发。     

Z24系列化合物体外致畸性的比较研究

Z 24系列化合物是基于Bcl-2蛋白三维结构通过计算机辅助药物设计所合成的5种癌相关蛋白拮抗剂,具有良好的体内外抗肿瘤活性;其中SU 5416具有抗肿瘤组织血管形成的药理活性[1],对Bcl-2蛋白有较强的拮抗作用。本研究采用中脑细胞微团培养试验比较这5种癌相关蛋白拮抗剂(SU 5416,Z     

薏苡仁多糖急性毒性及遗传毒性试验研究

目的了解薏苡仁多糖的毒理学安全性。方法小鼠急性毒性试验和遗传毒性试验（Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验）。结果薏苡仁多糖的小鼠经口LD50〉20g·kg^-1;在Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验中均呈阴性反应,未显示有遗传毒性作用。结论薏苡仁多糖基本无毒性。     

大豆多肽的毒性研究

目的研究大豆多肽的毒性。方法小鼠急性毒性试验、Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验、大鼠30d喂养试验。结果Ames试验、微核试验和精子畸形试验结果均为阴性;大鼠30d喂养试验结果显示该样品30d喂养对大鼠各项观察指标未见毒性作用。结论在本次实验条件下,大豆多肽为无毒物质,未显示有遗传毒性和亚急性毒性作用。     

灵芝孢子油急性毒性及致突变性研究

目的了解灵芝孢子油的毒理学安全性。方法小鼠急性毒性试验和遗传毒性试验(Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验)。结果灵芝孢子油的小鼠经口LD50>20 g.kg-1BW,为实际无毒级物质;在Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验中均呈阴性反应,未显示致突变作用。结论灵芝孢子油基本无毒性和无致突变性。     

安神胶囊的遗传毒性研究

目的 研究安神胶囊是否具有遗传毒性.方法 采用鼠伤寒沙门氏菌回复突变试验(Ames)的平板掺入法,小鼠骨髓嗜多染红细胞微核试验的间隔24 h两次给药法,以及小鼠精子畸变试验,对安神胶囊的遗传毒性进行全面的研究.结果 Ames试验中,各剂量组(5.00、2.50、1.25、0.62 mg/皿)的回复突变菌落数,与溶剂对照...     

A comparative study, with 40 chemicals, of the efficiency of the Salmonella assay and the SOS chromotest (kit procedure)

A comparison was made, for 40 compounds belonging to different chemical classes, of the mutagenicity as measured by the Salmonella assay and of the SOS-inducing potency as measured by the SOS chromotest kit procedure. It was found that most (78%) of the chemicals described as mutagens/carcinogens (14 compounds) were detected with a simplified Ames test procedure, using 3 strains (TA 97, TA 98, TA 100) and 3 concentrations of the tested material. The SOS chromotest, carried out following the recommendations of the commercially available kits, revealed that only 4 Ames test-positive compounds were mutagenic towards E. coli strain PQ 37.     

Screening of the food additive propionic acid for genotoxic properties

Genotoxic properties of the food additive propionic acid were analysed using the Escherichia coli DNA repair assay, the SOS chromotest, the Salmonella/microsome mutagenicity test, the sister chromatid exchange test in vitro and the micronucleus test in vivo. All tests except the DNA repair assay with E. coli yielded negative results. These data support other evidence that propionic acid is not mutagenic and that genotoxic events are unlikely to be the cause of forestomach lesions in rats fed propionic acid in the diet (Griem, Bundesgesundheitsblatt 1985, 28, 322).     

Genotoxicity of cyanobacterial extracts containing microcystins from Polish water reservoirs as determined by SOS chromotest and comet assay

Toxicity of cyanobacterial blooms, an increasing problem around the world, is connected to the increase in bloom samples containing microcystins, caused by excessive eutrophication of drinking- and recreational water reservoirs. Microcystins are the most common group of cyanobacterial hepatotoxins. In Poland they are produced mainly by the Microcystis genus. The toxicity of microcystins has been well documented, but investigation into their genotoxicity has been insufficient relative to the study of their overall toxicity. Therefore, the aim of this study was the estimation and comparison of the genotoxicity of cyanobacterial extracts with microcystins (CEMs) using the SOS chromotest (bacterial test) with Escherichia coli PQ37 and the comet assay with human lymphocytes. Cyanobacterial bloom samples were collected in the summer months from two Polish water reservoirs, one at Sulejów and one at Jeziorsko. The SOS chromotest, which used prokaryotic cells (without metabolic activation), and the comet assay, which used eukaryotic cells, both indicated the potential genotoxic effect of CEMs. Cyanobacterial extracts caused DNA damage in human lymphocytes in vitro. The maximum level of DNA damage was observed after 12 h incubation with CEMs. The bacterial test indicated a dependence of the degree of CEM genotoxicity, the composition, and the concentration of microcystins in each bloom sample examined with the time of exposure. Differences between the genotoxicity of cyanobacterial extract and the standard microcystin-LR were noticeable. This was probably caused by the interaction of different microcystin variants. The results showed that CEMs from Polish water reservoirs were genotoxic, which was reflected by the stimulation of the SOS repair system in bacterial cells (SOS chromotest) and by the damage induced in DNA in human lymphocytes (comet assay).     

Simplified protocol for evaluating the genotoxic risk of hospital wastewater

To evaluate the genotoxicity of hospital wastewater, we drew up a simplified protocol based on two well-known tests: the SOS chromotest and the Ames fluctuation test. Three concentrations of wastewater samples were directly tested without extraction or concentration. By fixing three significance levels in genotoxicity response for each test, we could classify the samples in five categories ranging from nongenotoxic to highly genotoxic. This simplified classification thus constitutes an invaluable help in making the nonscientist public aware of the genotoxic risk of hospital wastewater and can be applied in a screening approach to chemicals in the environment.     

Evidence of genotoxic substances in the Niagara river watershed

The SOS chromotest was used to detect genotoxicity of sediment samples from seven locations in the Welland River, Ontario, Canada, in December 1986 and April 1987. DMSO extracts of sediment samples from one location situated directly below the discharge pipe of a polyvinyl chloride plant showed a statistically significant (p < 0.01) genotoxic effect. It was concluded that genotoxic contaminants were associated with vinyl chloride contaminated sediments from this location. At a distance of 5 m downstream of the polyvinyl chloride plant's discharge, the mean SOS induction factor was 2.05, while 100 m further downstream the SOS induction factor had dropped to 1.54. The Ames test was used to detect genotoxicity of samples that gave positive responses in the SOS chromotest. The results of the Ames test were negative. This may suggest that the SOS chromotest is more sensitive than the Ames test for testing genotoxicity in these types of samples.     

红景天苷注射液遗传毒性的研究

目的：检测红景天苷注射液的遗传毒性。方法：应用微生物回复突变实验（Ames实验,5 000、500、50、5.0、0.5μg/皿）、体外培养CHO细胞染色体畸变实验（2 0001、000、500μg/mL）和小鼠骨髓微核实验法（1 500、750、375μg/kg）检测红景天苷注射液的遗传毒性。结果：红景天苷注射液对鼠伤寒沙门菌无致突变性,对体外培养CHO细胞染色体无致畸变作用,对ICR小鼠无诱发骨髓嗜多染红细胞微核的效应,三个实验结果均呈阴性。结论：红景天苷注射液不具有遗传毒性。     

The detection and comparison of the genotoxic effects of some nitro aromatic compounds by the umu and SOS chromotest systems.

Four nitroarenes were tested in two standard genotoxicity assay systems using three well-known bacterial tester strains. The results were as follows: 4-nitroquinoline l-oxide (4NQO) was positive in Quillardet and Hofnung's SOS chromotest using Escherichia coli strain PQ37 both in the presence and absence of microsomal (S9) supplements and in the Salmonella typhimurium umu tester strains NM2009 and NM3009, which express high levels of O-acetyltransferase (O-AT) and O-AT plus nitroreductase (NR) respectively. m-Nitrocinnamic acid (m-NCA) was weakly positive in strains NM2009 and NM3009, but negative in the SOS chromotest; m-dinitrobenzene (m-DNB) was weakly positive in strain NM2009, intermediate positive in strain NM3009, but negative in the SOS chromotest; 2,4-dinitrotoluene (2,4-DNT) was weakly positive in strain NM3009, but negative in strain NM2009 and in the SOS chromotest. However it still showed a dose-response relationship in strain NM2009. In view of these results, it is suggested that investigators planning to screen miscellaneous nitroarenes for their genotoxicity in the future should consider taking advantage of the increased sensitivity which is conferred on S. typhimurium strains NM2009 and NM3009 by virtue of their capacity to overexpress O-AT or O-AT and NR.     

Testing of SOS induction of artificial polycyclic musk fragrances in E. coli PQ37 (SOS chromotest)

Synthetic fragrances are widespread in the environment. Residues were found in animals, human tissues and breast milk. Therefore, six artificial polycyclic musk fragrances—Galaxolide, Tonalide, Celestolide, Phantolide, Cashmeran and Traseolide—were tested for SOS induction using the Escherichia coli PQ37 genotoxicity assay (SOS chromotest) in the presence (+S9) and absence (−S9) of an exogenous metabolizing system. All compounds tested exhibited no SOS inducing potency with the SOS chromotest. These results could be rated as one indicator of the biological inactivity of this group of compounds with respect to genotoxicity.     

崖柏精油致突变作用研究

摘 要 目的：采用鼠伤寒沙门菌回复突变（AMES）试验和哺乳动物微核试验对崖柏精油的遗传毒性进行评价。方法: AMES试验采用TA97、TA98、TA100和TA102四种菌株,对崖柏精油的致突变性进行评价。采用小鼠骨髓噬多染红细胞微核试验,对本品的染色体毒性进行评价。结果: 崖柏精油不同剂量组对TA97、TA98、TA100、TA102四种试验菌株,在加大鼠肝微粒体酶S9和不加S9的情况下,回复突变数均不超过溶剂对照组的1倍,差异无统计学意义（P<0.05）,为诱变阴性。微核试验表明,崖柏精油各剂量组对小鼠骨髓微核率无显著影响（P>0.05）。结论:崖柏精油无明显遗传毒性。