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首页> 外文期刊>Environmental toxicology and chemistry >BIOTRANSFORMATION MODEL OF NEUTRAL AND WEAKLY POLAR ORGANIC COMPOUNDS IN FISH INCORPORATING INTERNAL PARTITIONING
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BIOTRANSFORMATION MODEL OF NEUTRAL AND WEAKLY POLAR ORGANIC COMPOUNDS IN FISH INCORPORATING INTERNAL PARTITIONING

机译：掺入内部分配的鱼类中性和弱极性有机化合物的生物转化模型

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A model for whole-body in vivo biotransformation of neutral and weakly polar organic chemicals in fish is presented. It considers internal chemical partitioning and uses Abraham solvation parameters as reactivity descriptors. It assumes that only chemicals freely dissolved in the body fluid may bind with enzymes and subsequently undergo biotransformation reactions. Consequently, the whole-body biotransformation rate of a chemical is retarded by the extent of its distribution in different biological compartments. Using a randomly generated training set (n = 64), the biotransformation model is found to be: log (HLφ_(fish)) = 2.2 (±0.3)B - 2.1 (±0.2)V - 0.6 (±0.3) (root mean square error of prediction [RMSE] = 0.71), where HL is the whole-body biotransformation half-life in days, φ_(fish) is the freely dissolved fraction in body fluid, and B and Vare the chemical's H-bond acceptance capacity and molecular volume. Abraham-type linear free energy equations were also developed for lipid-water (K_(lipidw)) and protein-water (K_(protw)) partition coefficients needed for the computation of φ_(fish) from independent determinations. These were found to be 1) log K_(lipidw) = 0.77E - 1.10S - 0.47 A -3.52B + 3.37V + 0.84 (in L_(wat)/kg_(lipid) n = 248, RMSE = 0.57) and 2) log K_(prow) = 0.74E - 0.37S - 0.13A - 1.37B + 1.06V -0.88 (in L_(wat)/kg_(prot); n = 69, RMSE = 0.38), where E, S, and A quantify dispersive/polarization, dipolar, and H-bond-donating interactions, respectively. The biotransformation model performs well in the validation of HL (n = 424, RMSE = 0.71). The predicted rate constants do not exceed the transport limit due to circulatory flow. Furthermore, the model adequately captures variation in biotransformation rate between chemicals with varying log octanol-water partitioning coefficient, B, and V and exhibits high degree of independence from the choice of training chemicals. The present study suggests a new framework for modeling chemical reactivity in biological systems.
机译：提出了一种体内鱼类中性和弱极性有机化学物质的全身生物转化模型。它考虑内部化学分配，并使用亚伯拉罕溶剂化参数作为反应性描述符。假设只有自由溶解在体液中的化学物质才能与酶结合，随后发生生物转化反应。因此，化学药品的整体生物转化率因其在不同生物区室中的分布程度而受到阻碍。使用随机生成的训练集（n = 64），发现生物转化模型为：log（HLφ_（鱼））= 2.2（±0.3）B-2.1（±0.2）V-0.6（±0.3）（均方根预测的平方误差[RMSE] = 0.71），其中HL是指人体在几天内的生物转化半衰期，φ_（fish）是在体液中自由溶解的部分，而B和Vare是化学物质的H键接受能力，分子体积。还针对独立确定计算φ_（鱼）所需的脂质-水（K_（lipidw））和蛋白质-水（K_（protw））分配系数建立了亚伯拉罕型线性自由能方程。发现它们是1）log K_（lipidw）= 0.77E-1.10S-0.47 A -3.52B + 3.37V + 0.84（in L_（wat）/ kg_（lipid）n = 248，RMSE = 0.57）和2 ）log K_（prow）= 0.74E-0.37S-0.13A-1.37B + 1.06V -0.88（L_（wat）/ kg_（prot）; n = 69，RMSE = 0.38），其中E，S和分别量化分散/极化，偶极和氢键捐赠相互作用。该生物转化模型在HL的验证中表现良好（n = 424，RMSE = 0.71）。由于循环流量，预测的速率常数不超过传输极限。此外，该模型可以充分捕获具有不同对数辛醇-水分配系数B和V的化学物质之间生物转化率的变化，并且从训练化学物质的选择中显示出高度的独立性。本研究提出了一个用于模拟生物系统中化学反应性的新框架。

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