The input into the QIVIVE and Physiologically-Based kinetic and dynamic models of drug metabolising enzymes performance and their inter-individual differences significantly improve the modelling performance, supporting the development and integration of alternative approaches to animal testing. Bayesian meta-analyses allow generating and integrating statistical distributions with human in vitro metabolism data for quantitative in vitro-in vivo extrapolation. Such data are lacking on glutathione-S-transferases (GSTs). This paper reports for the first time results on the human variability of GST activities in healthy individuals, their tissue localisation and the frequencies of their major polymorphic variants by means of extensive literature search, data collection, data base creation and meta-analysis. A limited number of papers focussed on in vivo GST inter-individual differences in humans. Ex-vivo total GST activity without discriminating amongst isozymes is generally reported, resulting in a high inter-individual variability. The highest levels of cytosolic GSTs in humans are measured in the kidney, liver, adrenal glands and blood. The frequencies of GST polymorphisms for cytosolic isozymes in populations of different geographical ancestry were also presented. Bayesian meta-analyses to derive GST-related uncertainty factors provided uncertain estimates, due to the limited database. Considering the relevance of GST activities and their pivotal role in cellular adaptive response mechanisms to chemical stressors, further studies are needed to identify GST probe substrates for specific isozymes and quantify inter-individual differences.

中文翻译：

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谷胱甘肽-S-转移酶活性、组织分布和主要多态性变异的人类变异性：荟萃分析和化学风险评估的意义

QIVIVE 和基于生理学的药物代谢酶性能动力学和动态模型及其个体间差异的输入显着提高了建模性能，支持动物试验替代方法的开发和整合。贝叶斯荟萃分析允许生成统计分布并将其与人类体外代谢数据整合，以进行体外-体内定量外推。缺乏关于谷胱甘肽-S-转移酶（GST）的此类数据。本文通过广泛的文献搜索、数据收集、数据库创建和荟萃分析，首次报告了健康个体 GST 活动的人类变异性、组织定位和主要多态性变异的频率。数量有限的论文集中于人类体内 GST 的个体差异。通常报告了不区分同工酶的离体总 GST 活性，导致个体间的高变异性。人体细胞溶质 GST 的最高水平是在肾脏、肝脏、肾上腺和血液中测量到的。还提供了不同地理祖先人群中细胞溶质同工酶的 GST 多态性频率。由于数据库有限，用于推导 GST 相关不确定因素的贝叶斯元分析提供了不确定的估计。考虑到 GST 活性的相关性及其在细胞对化学应激物的适应性反应机制中的关键作用，需要进一步研究以确定特定同工酶的 GST 探针底物并量化个体间差异。