两种检测生殖细胞遗传毒性方法的比较

初级精母细胞染色体畸变分析试验(PSCAT)和精子畸形试验(SAMT)是目前国内外学者使用广泛的检测环境因素生殖遗传毒性的方法,但这两种方法检测环境诱变剂对生殖细胞遗传毒性的比较研究尚未见有报道。本文选用六种已知的环境诱变剂,对这两种方法的检出率及最低检出量(MDD)进行了比较,现将结果报道如下。     

病毒载体遗传毒性评价方法研究进展

随着基因治疗产品逐渐进入市场,迫切需要建立病毒载体介导的遗传毒性评价方法。目前应用广泛的病毒载体主要有2种：慢病毒载体和腺相关病毒载体。慢病毒载体能够稳定整合到宿主基因组中;而腺相关病毒载体基因组在宿主细胞核中主要以附加体形式存在,仍能以低频率随机整合到宿主细胞基因组中,其整合方式包括随机整合和靶向整合。本文对已有的病毒载体介导的遗传毒性评价方法,包括脱靶修饰的全基因组分析、整合位点分析、核型分析和评估细胞转化潜力试验等进行综述,并对建立准确快速的病毒载体介导的遗传毒性的评价体系予以展望,以期为进一步完善和研发新的病毒载体遗传毒性评价方法提供参考。     

低浓度苯的血液毒性及遗传毒性的研究进展

<正>苯不但在化工方面是一种极为重要的材料,其还是作为稀释剂、溶剂、萃取剂及燃料等,在农药生产、有机合成、制鞋等方面得到了广泛应用,所以苯属于一种污染源极大的环境污染物,可谓是无处不在。通过大量的动物实验以及相关的流行病学研究得知:若与过量的且达到一定程度的苯进行长时间的接触,便可对自身多种骨髓的造血功能造成影     

遗传毒性早期快速评价方法

遗传毒性评价是药物安全性评价的重要组成部分。如何早期、快速地获得药物可能的毒性反应数据,是当前遗传毒理学领域的研究热点之一。介绍几种目前应用比较广泛或有较好应用前景的早期、快速的遗传毒性评价方法,包括AmesII试验、Gadd45 Green Screen试验、高通量体外彗星试验和流式细胞术检测微核试验,主要围绕这些方法的基本原理、简要操作流程、预测毒性的可信度以及与传统方法相比的优缺点等展开。同时简要介绍计算机辅助毒性预测模型以及基因芯片技术在遗传毒性评价中的应用。     

仿制药中遗传毒性杂质的研究进展

我国是仿制药大国,在整个化学药品市场中仿制药占比约三分之二,其质量控制尤为重要。杂质控制是药品质量控制的重要一环,仿制药在杂质控制方面不仅要关注其参比药物中存在的杂质,更应结合实际生产工艺确定可能存在的需要加以控制的杂质。近年来,行业内对于仿制药中遗传毒性杂质的关注度不断提升。本文在宏观上对遗传毒性杂质的来源、检测方法等进行总结,以期对行业内的仿制药研发分析提供参考。     

麦绿素急性毒性和遗传毒性试验

麦绿素是大麦绿叶中提取的一种绿色粉末 ,含有丰富的植物蛋白、维生素、矿物质和叶绿素等 ,动物试验表明它具有抗氧化和抗衰老作用 ,现正作为保健食品被开发利用。为此 ,我们对其进行了急性毒性和遗传毒性的实验研究。1　材料与方法1 1　受试物　麦绿素由杭州某生物科技有限公司提供 ,为绿色粉末。用馏水配制成各剂量 ,混匀供试。1 2　试验动物　昆明种小鼠和ＳＤ大鼠由浙江省药检所实验动物中心提供。1 3　大、小鼠急性毒性试验　Ｈｏｒｎ氏法进行试验。选用体重 18～ 2 2ｇ昆明种小鼠及 180～ 2 2 0ｇＳＤ大鼠 ,大、小鼠分别随机分为 4组 …     

丙烯酰胺的遗传毒性研究

<正> 丙烯酰胺(AA)单体主要用于聚丙烯酰胺生产。这些高分子聚合体广泛用于给水和废水处理,食品加工(造糖造酒),石油开采和钻探,造纸选矿,化妆品添加剂,改良土壤性状以及用于科学研究和医药卫生等方面。各国学者对AA的毒性及神经毒作用进行过研究。近年来又对AA的“三致”作用的研究更为活跃,本文仅就AA的遗传毒性影响做一概述。一、基因突变分析 Bull等人使用AA做沙门氏菌/回变试验以确定它的致突性。在加或不加活化剂条件下、AA均未引起TA98,TA100,TA1535,TA1537,TA1538的回复突变。TA97,TA102的回复突变结果     

Z24系列化合物遗传毒性的优化筛选

目的：对Z24系列化合物进行遗传毒性优化筛选,从中选出毒性较低的候选新药作进一步开发.方法：采用Ames波动试验,SOS显色试验和双核细胞微核试验比较5种Z24系列化合物（Z24,SU5416,L1,L3和L4）的遗传毒性.结果：Ames波动试验结果表明除Z24外,其他4种化合物均显示致突变性;SOS显色试验则表明5种化合物均无致DNA原发损伤作用;双核细胞微核试验显示SU5416,L1,L3和L4具有致染色体断裂效应.结论：Z24是该系列化合物中最具开发前景的候选新药.     

苯乙腈类化合物遗传毒性的研究

苯乙腈类化合物遗传毒性的研究赵晓红，王毓美苯乙腈及其取代物是合成拟除虫菊酯类农药的重要中间产物，自１９７２年英国合成具有光稳定性的二氯苯醚菊酯以来，新型拟除虫菊酯杀虫剂便不断问世，并以其广谱、高效、低残留的特性得到广泛使用［１］。我国自８０年代以来也...     

对苯二胺的遗传毒性研究

对苯二胺的遗传毒性研究胡怡秀臧雪冰丘丰朱建华聂焱湖南省卫生防疫站（长沙４１０００５）对苯二胺（Ｐ－ｐｈｅｎｙｌｅｎｅｄｉａｍｉｎｅ）作为染发着色剂，普遍地存在于染发用品中，是一种较强的致敏原，小鼠急性经口ＬＤ５０为６５．３０ｍｇ／ｋｇ，属中等毒性物质...     

人源HepaRG肝细胞毒性与遗传毒性高通量筛选方法的初步建立

目的 利用正常人源肝细胞（HepaRG）和高内涵技术检测肝毒性标志物,并结合微核试验和单细胞凝胶电泳试验建立体外细胞毒性和遗传毒性的快速筛选平台。方法 选取适当的荧光探针Hoechst33342、DCFH-DA、Fluo4-AM、MitoTracker^® Red CMX Ros联合高内涵技术研究不同大黄蒽醌类单体（AQs）对HepaRG细胞活性氧簇（ROS）、胞内Ca²⁺含量及线粒体膜完整性等肝毒性标志物的影响,并开展高内涵法胞质分裂阻断法微核试验和高通量彗星电泳试验,综合评价AQs致肝细胞毒性及染色体、DNA损伤情况。结果 与对照组比较,HepaRG细胞经25.0 μg/mL大黄素、12.5和25.0 μg/mL芦荟大黄素、50和25.0 μg/mL大黄酚处理24 h后,胞内ROS含量显著增多;12.5和25.0 μg/mL芦荟大黄素和50.0 μg/mL大黄酸可引起胞内Ca²⁺含量显著增多;大黄素25.0 μg/mL、芦荟大黄素25.0 μg/mL、大黄酚50.0和25.0 μg/mL、大黄酸50.0和25.0 μg/mL组导致线粒体明显损伤（P<0.05、0.01）。与对照组比较,25.0 μg/mL大黄素诱导微核率、尾DNA含量和彗星尾距（OTM）数值均显著升高（P<0.05、0.01）;50.0 μg/mL大黄酚给药72 h后微核率显著升高（P<0.01）。结论 AQs的研究结果与现有文献报道基本相符。本研究成功建立肝细胞毒性和遗传毒性的联合快速筛选模型,有助于药物研发早期的毒性筛选。     

国内外大肠癌筛查现状及无创筛查方法进展

摘要： 大肠癌是严重威胁人类健康的恶性肿瘤之一, 其全球发病率和死亡率分居第3位和第2位。开展大肠癌筛查工作对大肠癌早发现、 早治疗具有重要意义。德国等经济发达国家上世纪七十年代就开始大肠癌筛查以降低其发生率和死亡率。我国也于1977年在部分大肠癌高发地区开展筛查工作, 近年在天津、 上海等大城市也开展了大肠癌筛查工作。笔者对国际和国内大肠癌筛查的现状进行综述, 探讨大肠癌筛查工作对降低大肠癌发病率和死亡率的意义, 并总结大肠癌筛查方法对筛查工作的影响。通过分析, 笔者认为国家健康计划、 科普宣传、 医保覆盖、 有效的监督机制以及合适的筛查方法是影响大肠癌筛查工作开展的重要因素。     

Evaluation of the GADD45α‐GFP GreenScreen HC assay for rapid and reliable in vitro early genotoxicity screening

Twenty‐two of Galderma's proprietary compounds were tested in the GADD45α‐GFP ‘GreenScreen HC’ assay (GS), the SOS‐ChromoTest and the Mini‐Ames to evaluate GSs performance for early genotoxicity screening purposes. Forty more characterized compounds were also tested, including antibiotics: metronidazole, clindamycin, tetracycline, lymecycline and neomycin; and catecholamines: resorcinol mequinol, hydroquinone, one aneugen carbendazim, one corticoid dexamethasone, one peroxisome proliferator‐activated receptor rosiglitazone, one pesticide carbaryl and two further proprietary molecules with in vitro genotoxicity data. With proprietary molecules, this study concluded that the GS renders the SOS‐ChromoTest obsolete for in vitro screening. The GS confirmed all results of the Mini‐Ames test (100% concordance). Compared with the micronucleus test, the GS showed a concordance of 82%. With known compounds, the GS ranked the potency of positive results for catecholamines in accordance with other genotoxicity tests and showed very reproducible results. It confirmed positive results for carbendazim, for tetracycline antibiotics and for carbaryl. The GS produced negative results for metronidazole, a nitroreduction‐specific bacterial mutagen, for dexamethasone (a non‐genotoxic apoptosis inducer), for rosiglitazone (a GADD45γ promoter inducer) and for clindamycin and neomycin (inhibitors of macromolecular synthesis in bacteria). As such, the GS appears to be a reproducible, robust, specific and sensitive test for genotoxicity screening. Copyright © 2012 John Wiley & Sons, Ltd.     

The genotoxicity of diaveridine and trimethoprim

We examined the genotoxicity of diaveridine and trimethoprim in the bacterial umu test, the bacterial reverse mutation test, the in vitro chromosome aberration test, the in vivo rodent bone marrow micronucleus test in two species, and the in vivo comet assay in five mouse organs. Both compounds were negative in the umu test (Salmonella typhimurium TA1535/pSK1002) and in the reverse mutation tests (S. typhimurium TA100, TA98, TA97, TA102, and Escherichia coli WP2 uvrA/pKM101) in the presence and absence of S9 mix. Diaveridine induced structural chromosome aberrations in cultured Chinese hamster CHL cells in the absence of a metabolic activation system, but not in the presence of a liver S9 fraction. No clastogenic activity in CHL cells was detected for trimethoprim. Bone marrow micronucleus tests in mice and rats conducted on diaveridine by single- and triple-oral dosing protocols were negative. The comet assay revealed that a single oral administration of diaveridine significantly induced DNA damage in liver, kidney, lung, and spleen cells, but not in bone marrow cells. The significant increase in migration values of DNA was reproducible with dose-response relationship. We suggest that the liver detoxifies the compound before it reaches the bone marrow, and that is why it is negative in the in vivo bone marrow micronucleus test. We concluded that diaveridine is genotoxic to mammalian cells in vitro and in vivo.     

Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles

Engineered nanoparticles (NPs) are widely used in different technologies but their unique properties might also cause adverse health effects. In reviewing recent in vitro and in vivo genotoxicity studies we discuss potential mechanisms of genotoxicity induced by NPs. Various factors that may influence genotoxic response, including physico-chemical properties and experimental conditions, are highlighted. From 4346 articles on NP toxicity, 112 describe genotoxicity studies (94 in vitro, 22 in vivo). The most used assays are the comet assay (58 in vitro, 9 in vivo), the micronucleus assay (31 in vitro, 14 in vivo), the chromosome aberrations test (10 in vitro, 1 in vivo) and the bacterial reverse mutation assay (13 studies). We describe advantages and potential problems with different methods and suggest the need for appropriate methodologies to be used for investigation of genotoxic effects of NPs, in vitro and in vivo.     

依布硒的生理活性及合成方法研究进展

有机硒类化合物是一类具有广泛生理活性的生物活性物质。依布硒是其代表化合物,它作为谷胱甘肽过氧化物酶的小分子模拟物可以被用于心脑血管疾病、炎症和噪声致听力损伤等多种疾病的治疗。笔者简要综述了依布硒的生理活性和合成方法的研究进展。     

抗艾滋病候选药物DCK系列化合物毒性评价*

目的:利用短期毒性检测方法对3种具有抗HIV活性的DCK系列化合物的一般毒性和特殊毒性进行检测。方法:采用MTT比色法、上下法和Ames波动试验对3种DCK系列化合物3-CH2NO2-4-CH3-DCK(N-DCK),3-CH2CN-4-CH3-DCK(C-DCK),3-F-4-CH3-DCK(F-DCK)的细胞毒性、急性毒性和遗传毒性进行检测。结果:3个化合物中,N-DCK和C-DCK对CHL细胞毒性相似,F-DCK细胞毒性最大,半数抑制浓度(IC50)分别为0.43,0.49,0.18 mg.mL-1;3种化合物对小鼠半数致死剂量(LD50)均>2 000 mg.kg-1;对沙门菌TA100诱变作用均与溶剂对照组相似,无明显致突变作用。结论:3种DCK系列化合物均为低毒物质,无明显遗传毒性。     

酶抑制剂类抗糖尿病药物的分子水平筛选方法研究进展

酶抑制剂类抗糖尿病药物是目前药物研究的热点,而药物筛选技术是制约此类抗糖尿病新药研发速度的关键步骤。主要从分子水平总结近年来报道的与糖尿病相关的酶抑制剂类候选药物的筛选方法,包括传统方法和前沿方法,着重介绍极具潜力的毛细管电泳法、质谱法、生物传感法和微通道筛选方法等。     

Selection of genotoxicity tests for risk assessment of effluents

Genotoxicity is one of the parameters within the whole effluent environmental risk procedure, an effect-based procedure developed in the Netherlands to supplement classical substance-specific risk assessment of effluents. To implement the genotoxicity parameter, one or more tests have to be selected for routine use on effluents. This paper deals with problems and considerations encountered during selection of genotoxicity tests. Tests were judged on: relevance, validation, detected genotoxic lesions, quantitative sensitivity, convenience, and cost-efficiency. Based on criterion detected genotoxic lesions and on criteria convenience and cost-efficiency, it is recommended to use at least a bacterial test which makes use of detection of the SOS pathway which is induced upon the occurrence of DNA damage. The criterion quantitative sensitivity is used in a laboratory study on effluent samples to select the most appropriate bacterial SOS pathway test. The range of detected genotoxic endpoints can be expanded by also including a more expensive test that detects clastogenesis and/or aneuploidy. In that case it seems wise first to establish the added value of such a test for the risk assessment of effluents, before deciding on further use. Furthermore, it is concluded that the presently available information on relevance and validation is of limited use for test selection. Finally, recommendations are made on test protocols and on pretreatment of effluent samples to optimize genotoxicity tests for effluent samples. Recommendations include data analysis, detection of the interference of cytotoxicity, extraction, the use of S9, concentration procedures, and filtration. © 2000 John Wiley & Sons, Inc. Environ Toxicol 15: 81–90, 2000     

药物遗传毒性研究相关要求进展

遗传毒性研究是药物非临床安全性评价的重要内容。人用药品注册技术要求国际协调会(ICH)对药物遗传毒性指导原则进行修订改版,于2008年颁布了S2(R1)人用药物遗传毒性试验和结果分析指导原则,该指导原则对于我国药物遗传毒性研究具有借鉴作用。文中简介了该指导原则修订的科学背景、主要修订内容,并讨论了目前我国药物遗传毒性研究中应关注的几个问题。