Evolutionary conservation of human drug targets in organisms used for environmental risk assessments
Evolutionary conservation of human drug targets in organisms used for environmental risk assessments
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DOI：
10.1021/es8005173
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发表时间：
2008-08-01
影响因子：
11.4
通讯作者：
Larsson, D. G. Joakim
中科院分区：
文献类型：
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作者：
Gunnarsson, Lina;Jauhiainen, Alexandra;Larsson, D. G. Joakim
药物通常在水生环境中的浓度很低。因此，明确分配给残留药物的环境影响与受影响野生动物物种中保守靶标的高亲和力相互作用一致，而不是与一般毒性作用一致。因此，给定物种中进化上高度保守的靶标与风险增加相关。在这项研究中，预测了16个物种中1318种人类药物靶标的直系同源物，其中几种与生态毒性测试相关。并对不同功能类别的靶分子的保守性进行了分析。斑马鱼与86%的药物靶点具有直系同源物，而在水蚤中只有61%是保守的，在绿色鱼中只有35%是保守的。预测的直系同源物的存在和不存在与已发表的关于不同物种中特定药物靶点相互作用潜力的实验数据非常一致。基于目标的保守性，我们建议人用药物的水环境风险评价应始终包括对水生脊椎动物的全面研究。此外，个别目标，特别是酶，是非常保守的，这表明在进化上遥远的生物体上的测试将与某些药物高度相关。我们建议，这些结果可以指导环境风险评估，提高识别物种敏感的某些类型的药物或其他污染物，通过明确的行动机制的可能性。此外，我们建议，结果可以用来解释现有的生态毒性数据的相关性。
Pharmaceuticals are typically found in very low concentrations in the aquatic environment. Accordingly, environmental effects clearly assigned to residual drugs are consistent with high affinity interactions with conserved targets in affected wildlife species rather than with a general toxic effect. Thus, evolutionarily well-conserved targets in a given species are associated with an increased risk. In this study orthologs for 1318 human drug targets were predicted in 16 species of which several are relevant for ecotoxicity testing. The conservation of different functional categories of targets was also analyzed. Zebrafish had orthologs to 86% of the drug targets while only 61% were conserved in Daphnia and 35% in green alga. The predicted presence and absence of orthologs agrees well with published experimental data on the potential for specific drug target interaction in various species. Based on the conservation of targets we propose that aquatic environmental risk assessments for human drugs should always include comprehensive studies on aquatic vertebrates. Furthermore, individual targets, especially enzymes, are well conserved suggesting that tests on evolutionarily distant organisms would be highly relevant for certain drugs. We propose that the results can guide environmental risk assessments by improving the possibilities to identify species sensitive to certain types of pharmaceuticals or to other contaminants that act through well defined mechanisms of action. Moreover, we suggest that the results can be used to interpret the relevance of existing ecotoxicity data.