高效液相色谱法构建定量结构-保留关系预测中药肝肾毒性组分的正辛醇-水分配系数值

doi:10.3724/SP.J.1123.2016.10044

色谱 ›› 2017, Vol. 35 ›› Issue (4): 432-438.DOI: 10.3724/SP.J.1123.2016.10044

高效液相色谱法构建定量结构-保留关系预测中药肝肾毒性组分的正辛醇-水分配系数值

项洋洋, 俞慧敏, 邓海山, 陈静雅, 张爱华, 池玉梅, 韩疏影

南京中医药大学, 江苏南京 210046

收稿日期:2016-10-22 出版日期:2017-04-08 发布日期:2013-07-30
通讯作者: 池玉梅,Tel:(025)85811053,E-mail:ymchii@njutcm.edu.cn;韩疏影,E-mail:njutcmhsy@163.com.
基金资助:
国家自然科学基金项目（81303311）；江苏省自然科学基金项目（BK20130958）；江苏省属高校自然科学基金项目（13KJB150030）；江苏高校优势学科建设工程项目（PAPD）；江苏高校品牌专业建设工程资助项目（PPZY2015A070）.

Prediction of n-octanol-water partition coefficients of hepatotoxicity/nephrotoxicity components in traditional herbs using quantitative structure-retention relationship models by high performance liquid chromatography

XIANG Yangyang, YU Huimin, DENG Haishan, CHEN Jingya, ZHANG Aihua, CHI Yumei, HAN Shuying

Nanjing University of Chinese Medicine, Nanjing 210046, China

Received:2016-10-22 Online:2017-04-08 Published:2013-07-30
Supported by:
National Natural Science Foundation of China (No. 81303311); Natural Science Foundation of Jiangsu Province (No. BK20130958); Jiangsu Provincial University Natural Science Foundation (No. 13KJB150030); Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); Top-Notch Academic Programs Project of Jiangsu Higher Education Institutions (No. PPZY2015A070).

摘要/Abstract

摘要：

构建了定量结构-保留关系（QSRR）测定马兜铃酸A、马兜铃酸B、马兜铃内酰胺及白黎芦醇的正辛醇-水分配系数（K_ow）。采用反相高效液相色谱（RP-HPLC）法，以甲醇-水为流动相，以16种已知K_ow值的酸性和中性苯系物为模型化合物，以保留时间两点校正法（DP-RTC）校正保留时间，并由Snyder-Soczewinski方程得100%水相保留因子k_w，建立了表观正辛醇-水分配系数K_ow″与k_w的定量关系（QSRR模型），并对模型进行了内、外部验证。结果显示，不同pH下的QSRR模型线性相关性良好（相关系数R²为0.980~0.987），内部验证（交叉验证相关系数R²_cv为0.982~0.988）和外部验证结果（6种验证化合物的相对误差RE为0.6%~10.9%）令人满意。将建立的QSRR模型应用于中药中4种潜在肝肾毒性化合物的K_ow测定，并与软件计算值、摇瓶法（SFM）实验值比较，结果显示该方法准确性更高，且简单快捷。该文提出的采用中性及酸性苯系物建立QSRR模型，通过对结构与性质相似的中药材组分进行RP-HPLC分析，得到各待测组分的保留时间即可获得其K_ow值的简便策略，解决了中药组分复杂且难以分离、无法通过SFM测定其K_ow值的问题，为通过定量-构效关系（QSAR）模型实现快速预测中药组分的肝肾毒性提供了可靠的K_ow数据。

关键词: 白黎芦醇, 定量结构-保留关系, 反相高效液相色谱, 马兜铃酸, 摇瓶法, 正辛醇-水分配系数

Abstract:

A quantitative structure-retention relationship (QSRR) was proposed to determine n-octanol-water partition coefficients (K_ow) of aristolochic acid A, aristolochic acid B, aristololactam and resveratrol in this paper. Sixteen acidic and neutral benzene analogues with reliable experimental K_ow data were chosen as model compounds for establishing linear relationship between the apparent n-octanol-water partition coefficient (K_ow″) and retention factor of 100% aqueous phase (k_w), which corresponds to retention factors of solutes using neat aqueous fraction as mobile phase. Methanol-water mixture was used as mobile phase at various mobile phase pH, and retention time (t_R) was rectified by a dual-point retention time correction (DP-RTC). The established models were evaluated by internal and external validations, respectively. QSRR models had good correlation coefficients at different mobile phase pH with correlation coefficients (R²) ranged from 0.980 to 0.987. Both internal (the cross-validated correlation coefficients (R_cv²) of 0.982-0.988) and external (0.6% ≤ relative errors (RE)≤10.9% for all the six verification compounds) validations showed satisfactory results. K_ow values of four hepatotoxic/nephrotoxic ingredients in traditional herbs were predicted by QSRR, and compared with the ones obtained by shake-flask method (SFM) and calculated by software as well. The method provided a convenient and rapid way to obtain reliable K_ow data. In addition, the proposed protocol realized simultaneous prediction for K_ow values of structure-similar components in traditional herbs merely through retention times, thereupon solved the dilemma of K_ow measurement by SFM resulting from inaccessibility of separating single component from complex herbs. These K_ow data can be applied in toxicity prediction of components in traditional herbs through quantitative structure-activity relationships (QSARs) in a follow-up study.

Key words: n-octanol-water partition coefficients (K_ow), aristolochics, quantitative structure-retention relationship (QSRR), resveratrol, reversed-phase high performance liquid chromatography (RP-HPLC), shake-flask method (SFM)

中图分类号:

O658

项洋洋, 俞慧敏, 邓海山, 陈静雅, 张爱华, 池玉梅, 韩疏影. 高效液相色谱法构建定量结构-保留关系预测中药肝肾毒性组分的正辛醇-水分配系数值[J]. 色谱, 2017, 35(4): 432-438.

XIANG Yangyang, YU Huimin, DENG Haishan, CHEN Jingya, ZHANG Aihua, CHI Yumei, HAN Shuying. Prediction of n-octanol-water partition coefficients of hepatotoxicity/nephrotoxicity components in traditional herbs using quantitative structure-retention relationship models by high performance liquid chromatography[J]. Chinese Journal of Chromatography, 2017, 35(4): 432-438.

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高效液相色谱法构建定量结构-保留关系预测中药肝肾毒性组分的正辛醇-水分配系数值

Prediction of n-octanol-water partition coefficients of hepatotoxicity/nephrotoxicity components in traditional herbs using quantitative structure-retention relationship models by high performance liquid chromatography

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