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Analysis of proteins cross-linked to DNA after treatment of cells with formaldehyde, chromate, and cis-diamminedichloroplatinum(II). 用甲醛、铬酸盐和顺式二胺二氯铂处理细胞后与DNA交联的蛋白质分析(II)。
Pub Date : 1989-01-01
C A Miller, M Costa

The proteins cross-linked to the DNA of cultured Chinese hamster ovary cells after exposure to cis-diamminedichloroplatinum(II) (cis-Pt), chromate, and formaldehyde were compared by two-dimensional (2D) gel electrophoresis, immunoblotting, and centrifugal assays that measured cross-link stability. Chromate and cis-Pt cross-linked seven of the same nonhistone proteins, such as actin, to DNA. In contrast, formaldehyde selectively formed histone-DNA cross-links. Immunoblotting experiments showed that all three chemicals cross-linked a 97-kDa nuclear protein to the DNA despite their different chemical reactivity with DNA and proteins. The chromate- and cis-Pt-induced cross-links were disrupted by thiourea, 2-mercaptoethanol, and EDTA, indicating that the metal could be chemically displaced from the cross-links. The formaldehyde-induced complexes required degradation with DNase 1 for the resolution of histones on 2D gels and were not chemically labile like the metal-induced cross-links. The agents and methodology used here could be applied to the study of additional nuclear proteins that bind or reside near the DNA.

通过二维(2D)凝胶电泳、免疫印迹和离心分析来比较暴露于顺式二胺二氯铂(cis-Pt)、铬酸盐和甲醛后培养的中国仓鼠卵巢细胞与DNA交联的蛋白质。铬酸盐和顺式铂将7种相同的非组蛋白(如肌动蛋白)与DNA交联。相反,甲醛选择性地形成组蛋白- dna交联。免疫印迹实验表明,尽管这三种化学物质与DNA和蛋白质的化学反应性不同,但它们都能将一个97 kda的核蛋白与DNA交联。铬酸盐和顺式pt诱导的交联被硫脲、2-巯基乙醇和EDTA破坏,表明金属可能从交联中被化学置换。甲醛诱导的复合物需要用DNase 1降解才能在2D凝胶上分解组蛋白,并且不像金属诱导的交联那样具有化学不稳定性。这里使用的试剂和方法可以应用于研究结合或驻留在DNA附近的其他核蛋白。
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引用次数: 0
Plasma membrane damage detected by nucleic acid leakage. 核酸渗漏检测质膜损伤。
Pub Date : 1989-01-01
E Fortunati, V Bianchi

Among the indicators of membrane damage, the leakage of intracellular components into the medium is the most directly related to the perturbations of the membrane molecular organization. The extent of the damage can be evaluated from the size of the released components. We have designed a protocol for the detection of membrane leakage based on the preincubation of cells with tritiated adenine for 24 h, followed by a 24-h chase in nonradioactive medium. The treatment takes place when the distribution of the precursor among its end products has reached the plateau, and thus the differences of radioactivity in the fractions obtained from the control and treated cultures (medium, nucleotide pool, RNA, DNA) correspond to actual quantitative variations induced by the test chemical. Aliquots of the medium are processed to determine which percentage of the released material is macromolecular, in order to distinguish between mild and severe membrane damage. The origin of the extracellular radioactivity can be recognized from the variations of RNA counts in the treated cells. DNA radioactivity is used to evaluate the number of cells that remain attached to the plates in the different conditions of treatment. By this means, generalized permeabilization of membranes to macromolecules is distinguished from complete solubilization of only a subpopulation of cells. We present some examples of application of the protocol with detergents (LAS, SDS, Triton X-100) and with Cr(VI), which damages cell membranes by a different mechanism of action.

在膜损伤的指标中,胞内组分向介质的渗漏与膜分子组织的扰动最直接相关。损坏的程度可以从释放部件的大小来评估。我们设计了一种检测膜渗漏的方案,该方案基于将细胞与氚化腺嘌呤预孵育24小时,然后在非放射性介质中进行24小时的追踪。当前体在其最终产物中的分布达到平台时,就进行处理,因此从对照和处理的培养物(培养基、核苷酸池、RNA、DNA)中获得的组分的放射性差异与测试化学品引起的实际定量变化相对应。处理等分的介质,以确定释放的物质中大分子物质的百分比,以区分轻度和严重的膜损伤。细胞外放射性的来源可以从处理细胞中RNA计数的变化中识别出来。DNA放射性用于评估在不同处理条件下仍附着在培养皿上的细胞数量。通过这种方法,将膜对大分子的普遍渗透与仅对一小部分细胞的完全溶解区分开来。我们提出了一些应用该方案的例子,洗涤剂(LAS, SDS, Triton X-100)和Cr(VI),它们通过不同的作用机制破坏细胞膜。
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引用次数: 0
Polybrominated naphthalene and diiodobenzene interactions with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver cytosol. 多溴萘和二碘苯与大鼠肝细胞质中2,3,7,8-四氯二苯并对二恶英特异性结合位点的相互作用
Pub Date : 1989-01-01
E N Cheung, J D McKinney

We provide evidence for two new classes of halogenated aromatic hydrocarbon ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or Ah) receptor: brominated naphthalenes and iodobenzenes. Polybrominated naphthalenes with four or more bromine atoms concentrated in lateral positions were shown to bind specifically and with high affinity (Kd approximately 10(-8) M) to the Ah receptor in rat liver cytosol preparations. The hexabrominated naphthalene isomers bind with high and nearly equal affinities but have been previously shown to have different toxicological properties. Possible explanations for these differences include differences in metabolism, antagonist versus agonist Ah receptor binding of some isomers, and the involvement of other binding sites in vivo that require different structural requirements. The moderate binding activity of the diiodobenzenes suggests that thyroid hormones should receive further study as possible endogenous ligands for the Ah receptor. It is difficult to explain the binding results with these two classes of compounds using previously developed molecular concepts for Ah receptor interactions based primarily on molecular size considerations.

我们为2,3,7,8-四氯二苯并对二恶英(TCDD或Ah)受体的两类新的卤代芳烃配体提供了证据:溴化萘和碘苯。在大鼠肝细胞质制剂中,具有四个或更多溴原子的多溴化萘具有特异性和高亲和力(Kd约为10(-8)M)与Ah受体结合。六溴化萘同分异构体具有高且几乎相等的亲和力,但先前已证明具有不同的毒理学性质。对这些差异的可能解释包括代谢的差异,一些异构体的拮抗剂与激动剂Ah受体的结合,以及体内其他需要不同结构要求的结合位点的参与。二碘苯的中等结合活性表明甲状腺激素可能作为Ah受体的内源性配体有待进一步研究。使用先前开发的基于分子大小考虑的Ah受体相互作用的分子概念,很难解释这两类化合物的结合结果。
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引用次数: 0
Do we find relevant parameters for in vitro cytotoxicity testing? 我们是否找到了体外细胞毒性试验的相关参数?
Pub Date : 1987-09-01
C A Reinhardt

The current strategy for the design of cytotoxicity tests is briefly reviewed in light of goals that need to be reached, and in the capacity of in vitro tests to fulfill the high public expectations for alternative methods to animal testing. Various cytotoxicity tests and parameters used for the assessment of topical toxicity and of neurotoxicity are chosen as examples and their relevance is discussed. Past experience with in vitro and short-term tests for mutagenicity shows not to look for one single supertest. A proposition for reasonable safety testing implies that a combined approach must be developed that integrates the results from a battery of cell tests and from structure-activity analyses as well as from kinetic and metabolic studies. The relevance of such an integrated approach must be aimed directly at the organisms that may be exposed.

根据需要达到的目标和体外试验的能力,简要审查了目前设计细胞毒性试验的战略,以满足公众对动物试验替代方法的高度期望。选择用于评估局部毒性和神经毒性的各种细胞毒性试验和参数作为例子,并讨论了它们的相关性。过去体外和短期诱变试验的经验表明,不要寻找单一的超级试验。关于合理的安全性测试的建议意味着必须开发一种综合方法,将一系列细胞测试和结构-活性分析以及动力学和代谢研究的结果结合起来。这种综合办法的相关性必须直接针对可能暴露的生物体。
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引用次数: 0
Photodynamic toxicity of hematoporphyrin derivatives to human keratinocytes in culture. 血卟啉衍生物对培养的人角质形成细胞的光动力毒性。
Pub Date : 1987-09-01
H Kappus, C Reinhold, M Artuc

Human keratinocytes in culture were able to take up hematoporphyrin derivatives (HPDs) used during photodynamic chemotherapy of tumors. In the absence of light, HPDs showed no cytotoxic effects to keratinocytes. However, after irradiation with visible light, HPDs induced immediate cytotoxicity as measured by the neutral red uptake assay. On the other hand, cell attachment as measured by protein estimation was not affected. When the cells treated with HPDs and irradiated with light were cultured for a further 72 h, they partially lost their ability to attach to the collagen surface. Most of the cells remaining attached after 72 h were no longer viable following treatment with HPDs and light. All parameters measured depended on the intracellular concentration of HPDs used (7-50 ng/10(5) cells) and the time of irradiation (0-30 min). These results suggest that human keratinocytes are a good model to study cytotoxic effects of photodynamically active drugs. Further, keratinocytes were unable to recover after damage caused by HPDs and light.

培养的人角质形成细胞能够吸收用于肿瘤光动力化疗的血卟啉衍生物(HPDs)。在没有光线的情况下,HPDs对角质形成细胞没有细胞毒性作用。然而,在可见光照射后,通过中性红色摄取测定,HPDs诱导了立即的细胞毒性。另一方面,通过蛋白质估计测量的细胞附着不受影响。当细胞用HPDs处理和光照射后,再培养72小时,它们部分失去了附着在胶原蛋白表面的能力。在HPDs和光照作用下,72 h后仍附着的大部分细胞不再存活。所有测量的参数取决于所用HPDs的细胞内浓度(7-50 ng/10(5)个细胞)和照射时间(0-30 min)。这些结果表明,人角质形成细胞是研究光动力活性药物细胞毒性作用的良好模型。此外,角化细胞在HPDs和光照造成的损伤后无法恢复。
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引用次数: 0
Assessment of peroxisome proliferation and liver growth-stimulating potential by nondirectly genotoxic compounds in cultured hepatocytes. 非直接基因毒性化合物对培养肝细胞中过氧化物酶体增殖和肝脏生长刺激潜能的评估。
Pub Date : 1987-09-01
F Bieri, W Stäubli, S Kelly, F Waechter, P Bentley

Previously, we have established that some peroxisome proliferators, a class of nongenotoxic hepatocarcinogens, are able to induce replicative DNA synthesis (RDS) in cultured hepatocytes. Hepatomegaly observed after short-term in vivo treatment correlated better with the ability to induce RDS than with the potency as peroxisome proliferator assessed in vitro. To clarify the challenging question of the limited sensitivity of primates to peroxisome proliferators, primary cultures of marmoset hepatocytes have been treated with nafenopin for some days. As expected from in vivo observations, no evidence for peroxisome proliferation could be observed. However, nafenopin induced a dose-dependent increase in the amount of RDS, but this induction was measurable only when the serum was absent from the culture medium. These results confirm that peroxisome proliferation and mitogenicity might be independent properties of peroxisome proliferators. Since in vivo the ability of compounds to induce RDS in liver cells is relevant to at least one key parameter of the hepatocarcinogenic response, it is suggested that measurement of RDS inducibility in cultured hepatocytes from different species might be relevant and useful to assess species differences in the liver tumor potency of nondirectly genotoxic compounds.

在此之前,我们已经证实一些过氧化物酶体增殖物(一类非遗传毒性的肝癌物质)能够在培养的肝细胞中诱导复制性DNA合成(RDS)。短期体内治疗后观察到的肝肿大与诱导RDS的能力相关,而与体外评估的过氧化物酶体增殖剂的效力相关。为了澄清灵长类动物对过氧化物酶体增殖物的有限敏感性这一具有挑战性的问题,研究人员用纳非诺平处理狨猴肝细胞的原代培养物已有几天。正如体内观察所预期的那样,没有观察到过氧化物酶体增殖的证据。然而,nafenopin诱导RDS的量呈剂量依赖性增加,但这种诱导只有在培养基中没有血清时才能测量到。这些结果证实,过氧化物酶体增殖和有丝分裂性可能是过氧化物酶体增殖体的独立特性。由于在体内,化合物在肝细胞中诱导RDS的能力至少与致肝癌反应的一个关键参数相关,因此,在不同物种培养的肝细胞中测量RDS诱导性可能与评估非直接遗传毒性化合物在肝肿瘤效力方面的物种差异相关且有用。
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引用次数: 0
Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals. 59种化学物质体外细胞毒性与体内急性毒性的比较。
Pub Date : 1987-09-01
R H Clothier, L M Hulme, M Smith, M Balls

The in vitro cytotoxicities of 59 chemicals, expressed as ID50 values (i.e., concentrations of test chemicals that reduced the final cellular protein content of test cultures by 50% in comparison with appropriate solvent control cultures) and obtained using murine 3T3-L1 cells and the FRAME kenacid blue method, have been compared with rat oral and mouse intraperitoneal (ip) LD50 values. A better in vivo/in vitro correlation was obtained for the 59 chemicals with mouse ip LD50 values (r = .80) than with rat oral LD50 values (r = .76), but the best in vivo/in vitro correlation was found when the most toxic of the rat and mouse values were used in the comparison (r = .81).

用小鼠3T3-L1细胞和FRAME ken酸蓝法获得的59种化学物质的体外细胞毒性,用ID50值表示(即,与适当的溶剂对照培养物相比,试验化学物质的浓度使试验培养物的最终细胞蛋白含量降低50%),并与大鼠口服和小鼠腹腔内(ip) LD50值进行了比较。59种化学物质与小鼠体内LD50值(r = 0.80)的体内外相关性优于与大鼠口服LD50值(r = 0.76),但以大鼠和小鼠毒性最大值进行比较时,体内外相关性最好(r = 0.81)。
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引用次数: 0
Fifth International Workshop on In Vitro Toxicology. Schloss Elmau, West Germany, November 1988. Proceedings. 第五届体外毒理学国际研讨会。1988年11月,西德埃尔茂城堡。程序。
Pub Date : 1987-09-01
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引用次数: 0
Validation of the red blood cell test system as in vitro assay for the rapid screening of irritation potential of surfactants. 验证红血球测试系统作为快速筛选表面活性剂刺激潜能的体外试验。
Pub Date : 1987-09-01
W J Pape, U Pfannenbecker, U Hoppe

An in vitro red blood cell assay (RBC assay) is presented that allows one to estimate irritation potentials of tensides and detergents. The estimation is based on the differentiation between cell membrane lysis and cell protein denaturation. Both effects are measured photometrically by use of the inherent native dye oxyhemoglobin (HbO2). Besides hemolysis (H50) as a test parameter, the denaturation index DI is introduced, which is defined to be equal to 100% at a concentration of 30 mol sodium dodecylsulfate (SDS) per mole HbO2 as internal standard. The HbO2 release (H50), its denaturation (DI), and the ratio of both parameters (L/D ratio) are used to characterize the in vitro effects of surfactants. All data, including the L/D ratio are compared with in vivo data on eye irritancies, evaluated according to OECD Guideline #405 for testing chemicals, and with other published results from in vivo experiments. The good correlation of the L/D ratio of a broad range of 100 marketable shampoos with their corresponding Draize data (r = .806, p less than .0001) allows one to predict eye irritation potentials from another 20 commercially available shampoos in a blind trial with highly significant rank correlations to their in vivo irritancies (rs = .911, p less than .0001). Nearly similar good correlations were obtained by comparing ranks of in vivo and in vitro data of 16 anionic surfactants. All correlations found were significant (rs greater than .80 and p less than .0001). The RBC assay is an inexpensive, rapid, irritancy screening test that provides reliable results with good reproducibility. The test helps to reduce or even avoid animal testing in this application.

体外红细胞测定(RBC测定)提出,允许一个估计张力和洗涤剂的刺激电位。估计是基于细胞膜裂解和细胞蛋白变性之间的区别。这两种效应都是用固有的天然染料氧合血红蛋白(HbO2)光度法测量的。除了溶血(H50)作为测试参数外,还引入了变性指数DI,定义为在每摩尔HbO2浓度为30 mol十二烷基硫酸钠(SDS)为内标时,DI等于100%。用HbO2的释放量(H50)、变性率(DI)和两者的比值(L/D比)表征表面活性剂的体外作用。将所有数据(包括L/D比率)与根据经合组织第405号化学品测试指南评估的体内眼睛刺激数据进行比较,并与其他已发表的体内实验结果进行比较。广泛的100种市场上销售的洗发水的L/D比率与其相应的Draize数据(r = 0.806, p小于0.0001)的良好相关性允许人们在盲试验中预测另外20种市售洗发水的眼睛刺激电位,其体内刺激具有高度显著的等级相关性(rs = 0.911, p小于0.0001)。通过比较16种阴离子表面活性剂的体内和体外数据,得到了几乎相似的良好相关性。所有发现的相关性均显著(rs大于0.80,p小于0.0001)。红细胞分析是一种廉价、快速、刺激筛选试验,可提供可靠的结果和良好的重复性。该测试有助于减少甚至避免在此应用程序中进行动物测试。
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引用次数: 0
Validation of alternative toxicity test systems: lessons learned and to be learned. 替代毒性测试系统的验证:已吸取的教训和需要吸取的教训。
Pub Date : 1987-09-01
M Balls, R Clothier

Validation in the context of in vitro toxicity tests is defined, and various aspects of the validation process are discussed, including the design and conduct of interlaboratory validation schemes; the selection of tests, participating laboratories, and test chemicals; the selection and use of in vivo data; in vivo/in vitro data comparison; the question of "false" results; in vitro cytotoxicity as a predictor of actual lethal toxicity; and the validation of alternatives to the Draize eye irritancy tests. It is concluded that a thorough reevaluation of current practice is essential if the promise and potential of nonanimal toxicity tests are to be fully realized and if valid alternative tests acceptable to regulatory agencies are to be developed.

定义了体外毒性试验背景下的验证,讨论了验证过程的各个方面,包括实验室间验证方案的设计和实施;选择测试、参与实验室和测试化学品;体内数据的选择和使用;体内/体外数据比较;“假”结果的问题;体外细胞毒性作为实际致死毒性的预测因子;以及验证Draize眼睛刺激测试的替代方案。结论是,如果要充分实现非动物毒性试验的希望和潜力,如果要开发监管机构可接受的有效替代试验,就必须对目前的做法进行彻底的重新评价。
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引用次数: 0
期刊
Molecular toxicology
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