毒理基因组学在肾毒性研究中的应用进展

肾脏是体内最重要的排泄器官,也是外源性毒物在体内的主要代谢器官之一。很多化合物(药物)进入体内可引起肾脏损伤。国内外学者利用体内或体外模型对肾毒性作用及其机制进行了研究[1]。近年来,毒理基因组学(toxicogenomics)的快速发展对毒性评价的模式、毒理学的研究方法产生了     

毒理芯片技术在药物毒理学中的应用

近年来，生物芯片技术在生物学领域中得到了飞速的发展，并已开始用于药物毒理学领域：包括基因芯片技术在药物毒理机制研究中的应用；发现毒理学中药物毒性的预到；化学物代谢特性分析与评价；化学致癌物筛选和识别，以及药物临床前安全性评价等。本文重点介绍了毒理芯片技术及其在药物毒理机制和药物毒性预测中的应用，并简单阐述了其在药物毒理上应用的局限性。     

毒理基因组学在临床前药物致癌性评价中的研究进展

毒理基因组学是将基因组信息和技术应用于毒理学研究的一门新兴学科,是一种有效的毒理学动物实验替代方法,其主要技术手段为高通量的基因芯片技术,其快速发展为药物致癌性评价开辟了新的途径。文中综述了临床前药物致癌性评价的现状以及毒理基因组学在非遗传毒性药物临床前致癌性评价中的研究进展,包括肝脏基因表达谱分析鉴定致癌物和非致癌物,经典致癌物短期动物实验的基因表达谱预测致癌物,基于不同致癌机制的基因表达谱预测致癌物,非遗传毒性药物致癌机制的研究,以及基因芯片数据的质量控制和分析五个方面,并探讨了存在的问题和发展前景。     

毒理基因组学

自从人类基因组计划实现初步的目标后 ,很快在相关的领域产生了积极的影响。先是在环境科学领域建立了环境基因组计划 (ｔｈｅＥｎｖｉｒｏｎｍｅｎｔａｌＧｅｎｏｍｅＰｒｏｊｅｃｔ) [1] ,加速了对环境应激的基因多态性的研究[2 ] 。继而在毒理学领域启动了毒理基因组学研究计划 (ｔｈｅＴｏｘｉｃｏｇｅｎｏｍｉｃｓＲｅｓｅａｒｃｈＰｒｏｇｒａｍ) [3 ] ,将微点阵技术引入到毒理学研究中 ,形成了一个新的毒理学分支学科[4 ] 。毒理基因组学的基本任务 ,是利用人类基因组的资料 ,帮助筛选和鉴别潜在的环境遗传毒物 ,并在基因水平上闸明…     

毒理基因组学与DNA微阵列技术的应用

近几年来 DNA微阵列和 DNA芯片技术得到了迅速发展 ,并开始应用于毒理学研究 ,本文介绍了微阵列技术如何与毒理学研究相结合并应用于危险度评估 ,并形成一个新的研究领域毒理基因组学     

当前遗传毒理学的研究动态

近年来,随着毒理学和遗传学的发展,特别是随着基因组学、蛋白质组学等的研究进展,人们对生物细胞基因组结构、表达、调控及其与表型(包括毒性效应、疾病、机体易感性等)关系的认识不断深化,遗传毒理学作为主要研究环境因素对基因组效应的一门毒理学分支学科,目前正处于总结、反思过去,分析现状特别是存在的问题,积极探索未来发展的时期。现从基础理论、遗传毒性测试方法和应用研究三方面扼要概述遗传毒理学的进展、存在的问题或研究动向,供关注该领域发展的同行参考。1遗传毒理学基础理论方面的研究1.1遗传毒理学的几个基本概念(1)广义的遗…     

基因芯片技术在药物毒理学研究中的应用

随着基因芯片技术的发展,逐渐被应用于研究药物的毒性作用及其作用机制。与传统的药物毒理学研究方法比较,基因芯片技术具有周期短、高通量的优势,基因芯片技术的介入也进一步推动了药物毒理学研究的发展。从新药的筛选、毒理安全性评价到临床应用,基因芯片技术将成为贯穿整个药物毒理学研究的重要技术。就近期基因芯片技术在药物毒理学研究中的应用成果进行了回顾总结。     

超微结构病理学在药物非临床安全性评价毒理学研究中的应用现状和关注点

超微结构病理学是药物非临床毒理学研究中毒性病理学评估的重要辅助工具。简要介绍了超微结构病理学在药物非临床安全性评价毒理学研究中的应用现状和关注点,并举例说明了透射电子显微镜等超微结构病理学技术在药物非临床安全性评价中的应用。目前,超微结构病理学技术在药物非临床毒理研究中虽然使用率不高,却是非临床毒理学研究中毒性病理学评估的重要辅助工具,可用于对光学显微镜检查结果的进一步研究,以作为早期药物发现和非临床安全性评价毒理学研究的有益补充。在使用超微结构病理学技术进行药物非临床毒理学研究时,应关注其使用的必要性、良好实验室规范（GLP）依从性、专业性、科学性和使用局限性等方面。     

药物毒理学的研究进展

近年来,国内药物毒理学发展迅速,在研究思路和观念、技术和手段、策略和方法上发生了巨大转变,其主要表现为;研究过程和实验操作逐步走向规范化、标准化;逐步采用体外筛选评价模型代替整体动物实验;在药物开发、申报、临床监测的各个环节药物毒理学发挥着主动指导作用;随着现代生物医药技术的发展,特别是基因组学、蛋白质组学和代谢组学等的出现为药物毒理学的发展赋予了新的契机,使之经历了研究思路、方法、技术和理念的巨大转变。药物毒理学是根据药物的理化特性,运用毒理学的原理和方法,对其进行全面系统的安全性评价并阐明其毒性作用机制,以便降低药物对人类健康的危害。毒理学是一门研究外源因素(化学、物理、生物因素)对生物系统的有害作用的应用学科。是一门研究化学物质对生物体的毒性反应、严重程度、发生频率和毒性作用机制的科学,也是对毒性作用进行定性和定量评价的科学。是预测对人体和生态环境的危害,为确定安全限值和采取防治措施提供科学依据的一门学科。然而药物毒理学是研究药物毒性的作用机制,并对药物进行全面系统的安全性评价的一门学科,在指导临床合理用药,降低药物不良反应及减少因药物毒性而导致的新药开发失败等方面起到了至关重要的作用。因此药物毒理成为现阶段我国研发人员所要攻克的重要问题。     

计算毒理学与中药毒性预测的研究进展

计算毒理学近几年受到美国及欧盟相关立法及研究机构的重视,被越来越多地应用于新药毒性预测及环境化合物的安全评价。化合物毒性预测方法可分为两大类:一类是以化合物本身为基础的计算方法,主要是研究结构与毒性的定量关系;另一类是以毒性靶分子结构为基础的方法,又被称为分子机理法。我国在环境化合物的毒性预测、算法及建立构效模型上取得进展,将计算毒理学应用于新药研发已经起步,但尚未见到计算毒理学用于中药及其化合物毒性的研究。而国外在天然化学成分的毒性预测、结构毒性关系的研究上取得了一些进展。由于中药化学成分与人工合成化合物在化学空间的差别,同时中药是多组分的混合物,毒性预测有较大的挑战性。随着组学技术被更多地应用于化合物毒性的研究,计算毒理学在中药毒性研究中的应用也有新的机遇。     

Procedures available to examine the immunotoxicity of chemicals and drugs

The discipline of immunology should provide toxicology with sensitive models to assess toxicity as well as provide better safety assessment. More information on correlations between immune function and host resistance changes and a more standardized panel of methods for immunotoxicity screening will add further credence to the already impressive immunotoxicology data base. Research efforts are needed to evaluate newer in vitro methods with microsome activation systems to screen chemicals for immunotoxicity, to evaluate chemicals for induction of hypersensitization or allergy, and to better determine whether there are chemical structure activity relationships for chemically induced immunotoxicity. The studies described here represent preliminary examples of these approaches.     

Toxicity and carcinogenicity of nickel compounds

The toxicity and carcinogenicity of nickel compounds are considered in three broad categories: (1) systemic toxicology, (2) molecular toxicology, and (3) carcinogenicity. The systemic toxicity of nickel compounds is examined based upon human and animal studies. The major organs affected are discussed in three categories: (1) kidney, (2) immune system, and (3) other organs. The second area of concentration is molecular toxicology, which will include a discussion of the chemistry of nickel, its binding to small and large molecular weight ligands, and, finally, its cellular effects. The third major area involves a discussion of the carcinogenicity and genotoxicity of nickel compounds. This section focuses on mechanisms, using studies conducted in vivo and in vitro. It also includes a discussion of the assessment of the carcinogenicity of nickel compounds.     

Perfluoroalkyl acids: a review of monitoring and toxicological findings.

In recent years, human and wildlife monitoring studies have identified perfluoroalkyl acids (PFAA) worldwide. This has led to efforts to better understand the hazards that may be inherent in these compounds, as well as the global distribution of the PFAAs. Much attention has focused on understanding the toxicology of the two most widely known PFAAs, perfluorooctanoic acid, and perfluorooctane sulfate. More recently, research was extended to other PFAAs. There has been substantial progress in understanding additional aspects of the toxicology of these compounds, particularly related to the developmental toxicity, immunotoxicity, hepatotoxicity, and the potential modes of action. This review provides an overview of the recent advances in the toxicology and mode of action for PFAAs, and of the monitoring data now available for the environment, wildlife, and humans. Several avenues of research are proposed that would further our understanding of this class of compounds.     

中药注射剂免疫毒性评价研究进展

为考察中药注射剂免疫毒性评价研究的发展近况,就近年来文献报道的中药注射剂免疫毒性相关实验研究从免疫毒性评价技术、类过敏反应研究、长期毒性评价中免疫指标的观察3个方面进行了概括,发现虽然在敏感动物选择、过敏原检查、新技术应用、细胞实验研究、吐温-80与类过敏反应关系及长期毒性试验中免疫系统指标观察等方面取得了一定进步,但仍需完善评价方法及指导原则,进一步加强提高操作规范性等方面。     

Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing.

The de minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle of Threshold of Toxicological Concern (TTC) has been developed and is now used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, industry and regulators, since it would preclude extensive toxicity evaluations when human intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such threshold. In this review, the possibility of defining a TTC for chemical substances present in the diet was examined for general toxicity endpoints (including carcinogenicity), as well as for specific endpoints, namely neurotoxicity and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to have either a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster et al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro et al. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances showing any effect which could point to developmental toxicity as broadly defined by the US were recorded in the database. Additionally, endocrine toxicity and allergenicity were addressed as two separate cases, using different approaches and methodology. The distributions of NOELs for the neurotoxicity, developmental neurotoxicity and developmental toxicity endpoints were compared with the distribution of NOELs for non-specific carcinogenic endpoints. As the immunotoxicity database was too limited to draw such a distribution of immune NOELs, the immunotoxicity endpoint was evaluated by comparing immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available) with non-immune NOELs (or LOELs), in order to compare the sensitivity of this endpoint with non-specific endpoints. A different methodology was adopted for the evaluation of the endocrine toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential impact on human health, based on their contribution to the overall exposure, and their estrogenic potency relative to endogenous hormones. The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e. labelling) than the Threshold of Toxicological Concern approach. (ABSTRACT TRUNCATED)     

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

Immune function tests for hazard identification: a paradigm shift in drug development

Routine immune function testing in preclinical drug development was established as a regulatory requirement in June of 2000 under the Committee of Proprietary Medicinal Products (CPMP) Note for Guidance on Repeated Dose Toxicity (CPMP/SWP/1042/99). The purpose of the more stringent approach to immunotoxicology testing was to better identify unintended immunosuppression; however, the requirement was met with much discussion and debate. At the center of the discussion was an attempt to reconcile opposing regulatory directives from agencies outside of Europe that adhere to a more selective, weight-of-evidence approach to functional evaluations. Uncertainty over the predictive value of the recommended immune function tests relative to conventional toxicology parameters prompted an investigation by the International Committee on Harmonization (ICH). The results of a preliminary, industry-wide survey indicated that only a low percentage of pharmaceuticals adversely affect immune function without alterations to standard toxicology parameters. Expected ICH guidelines will ultimately determine to what extent and for what purpose immune function tests will be conducted. In the meantime, optimization of the recommended immune function tests is ongoing. The T-cell dependent antibody response (TDAR) by either conventional Sheep Red Blood Cell (SRBC) plaque assay or by the modified ELISA method using either SRBC or keyhole limpet hemocyanin (KLH) as antigen is being extensively evaluated to determine best practices and procedures for preclinical immunotoxicity evaluations. This review addresses some aspects of the debate concerning the appropriateness of immune function tests for hazard identification, along with recommendations for optimizing TDAR methodology to ensure adequate sensitivity and predictability in risk assessments for immunotoxicity.     

药物安全性研究中免疫系统的病理学评价

免疫系统是一个复杂的、涉及多个器官的系统,自身易受年龄、性别、环境等多个因素的影响,其正常的生理变异较大,因此在临床前安全性研究中评估药物所致的免疫毒性是一个巨大的挑战。目前,免疫系统的组织形态学评价是确定免疫毒性公认的基石。就免疫系统病理学评价相关的指导原则,以及胸腺、脾脏、淋巴结等重要免疫器官的病理学评价进行简要论述,以帮助毒性病理学家准确和一致性评价免疫系统中预期的或意外的药物所致的毒性改变。     

What's so special about the developing immune system?

The evolution of the subdiscipline of developmental immunotoxicology (DIT) as it exists today has been shaped by significant regulatory pressures as well as key scientific advances. This review considers the role played by legislation to protect children's health, and on the emergence of immunotoxcity and developmental immunotoxicity guidelines, as well as providing some context to the need for special attention on DIT by considering the evidence that the developing immune system may have unique susceptibilities when compared to the adult immune system. Understanding the full extent of this potential has been complicated by a paucity of data detailing the development of the immune system during critical life stages as well as by the complexities of comparisons across species. Notably, there are differences between humans and nonhuman species used in toxicity testing that include specific differences relative to the timing of the development of the immune system as well as more general anatomic differences, and these differences must be factored into the interpretation of DIT studies. Likewise, understanding how the timing of the immune development impacts on various immune parameters is critical to the design of DIT studies, parameters most extensively characterized to date in young adult animals. Other factors important to DIT, which are considered in this review, are the recognition that effects other than suppression (e.g., allergy and autoimmunity) are important; the need to improve our understanding of how to assess the potential for DIT in humans; and the role that pathology has played in DIT studies in test animals. The latter point receives special emphasis in this review because pathology evaluations have been a major component of standard nonclinical toxicology studies, and could serve an important role in studies to evaluate DIT. This possibility is very consistent with recommendations to incorporate a DIT evaluation into standard developmental and reproductive toxicology (DART) protocols. The overall objective of this review is to provide a 'snapshot' of the current state-of-the-science of DIT. Despite significant progress, DIT is still evolving and it is our hope that this review will advance the science.     

Immune function testing of human pharmaceuticals: regulatory overshoot?

Suppression of the activity of the immune system can result in decreased resistance to (opportunistic) infection and cancer. Experimental animal studies have identified many immunotoxic agents, but data on unintended immuno-toxicity of human pharmaceuticals are limited. To enhance the sensitivity of the non-clinical screening of human pharmaceuticals, immunotoxicity endpoints in standard toxicity studies, as well as an immune function study, are requested by the EU, incorporating a T-cell-dependent antigen response in the first screening phase. Authorities from other areas in the world follow similar lines for immunotoxicity testing, but differ in whether or not the functional assay is seen as a primary requisite or can be secondary to other factors or observations. Based on a limited survey in the framework of the International Conference on Harmonization, the European position has been reconsidered to negotiate a broad cause-for-concern approach. The relevance of functional testing of the immune system to show effects of human pharmaceuticals is shown in this review. There is certainly a need for more in-depth testing of the integrity of the immune system and a cause-for-concern approach is, therefore, needed. A broad category is the number of compounds that might interact via binding to receptor sites at the broadly taken population of leukocytes (e.g., lymphocytes, macrophages). Criteria to differentiate among compounds in this category have yet to be ascertained.