Saxena A K, Devillers J, Bhunia S S, Bro E
a CSIR-CDRI , Lucknow , India.
b CTIS , Rillieux La Pape , France.
SAR QSAR Environ Res. 2015;26(7-9):757-82. doi: 10.1080/1062936X.2015.1090749.
The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase.
农药及其代谢产物对内分泌系统的潜在影响是野生动物和人类健康的主要关注点。在此背景下，唑类农药因其对细胞色素P450芳香化酶的抑制潜力而备受关注。细胞色素P450芳香化酶（CYP19）分别催化雄烯二酮和睾酮转化为雌酮和雌二醇。因此，芳香化酶调节雌激素平衡，这不仅对雌性至关重要，对雄性生理机能，包括性腺功能也至关重要。其抑制作用会影响人类和野生动物的生殖器官、生育能力和性行为。多项研究表明，唑类农药能够抑制人类和鱼类的芳香化酶，但关于鸟类的信息却很缺乏。因此，评估三种不同鸟类物种（即原鸡、日本鹌鹑和斑胸草雀）中唑类对芳香化酶的抑制作用似乎很有意义。由于这些鸟类物种中缺乏芳香化酶的晶体结构，因此利用人类芳香化酶（hAr）（pdb：3EQM）的晶体结构构建了各个鸟类物种的同源模型，该晶体结构与原鸡（82.0%）、斑胸草雀（81.9%）和日本鹌鹑（81.2%）具有高度的序列相似性。还设计了一个与虹鳟鱼（81.9%）的同源模型用于比较。选择了每个鸟类和鱼类物种的同源建模芳香化酶以及人类芳香化酶的晶体结构，用于对接46种结构多样的唑类及相关化合物。我们发现这些化学物质在不同芳香化酶上的对接行为大致相同。我们还证明，结合得分值与现有的芳香化酶抑制数据之间存在可接受的相关性。这意味着基于鸟类和鱼类物种得出的同源模型可用于近似唑类对其芳香化酶的潜在抑制作用。
