Multiple linear regression analysis indicates association of P-glycoprotein substrate or inhibitor character with bitterness intensity, measured with a sensor
Multiple linear regression analysis indicates association of P-glycoprotein substrate or inhibitor character with bitterness intensity, measured with a sensor
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多元线性回归分析表明 P-糖蛋白底物或抑制剂特性与传感器测量的苦味强度之间的关联
DOI：
10.1002/jps.24232
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发表时间：
2015
影响因子：
3.8
通讯作者：
Takuo Ogihara
中科院分区：
文献类型：
--
作者：
Kentaro Yano;Suzune Mita;Kaori Morimoto;Tamami Haraguchi;Hiroshi Arakawa;Miyako Yoshida;Fumiyoshi Yamashita;Takahiro Uchida;Takuo Ogihara
P-糖蛋白（P-gp）调节多种药物在胃肠道的吸收和在肿瘤组织中的蓄积，但P-gp的底物识别基础尚不清楚。苦味苯硫脲，刺激味觉受体2成员38（T2 R38），增加P-gp活性，是P-gp的底物。这使我们假设苦味强度可能是P-gp抑制剂/底物状态的预测因子。在这里，我们测量了一个面板的P-gp底物和nonsubstrates与各种味觉传感器的苦味强度，并使用多元线性回归分析来研究P-gp抑制剂/底物状态和各种物理性质之间的关系，包括与味觉传感器测量的苦味强度。由于所有味觉传感器的输出具有显著的相关性，我们计算了第一主成分分析得分（PC 1）作为苦味的代表值。P-gp底物显示出比非P-gp底物显著更大的平均苦味强度。P-gp底物的Km值与分子量、logP和PC 1值相关，线性回归方程的决定系数（R2）为0.63。这种关系可能有助于在药物发现的早期阶段预测P-gp底物状态。© 2014 Wiley Periodicals，Inc.和美国药剂师协会
P-glycoprotein (P-gp) regulates absorption of many drugs in the gastrointestinal tract and their accumulation in tumor tissues, but the basis of substrate recognition by P-gp remains unclear. Bitter-tasting phenylthiocarbamide, which stimulates taste receptor 2 member 38 (T2R38), increases P-gp activity and is a substrate of P-gp. This led us to hypothesize that bitterness intensity might be a predictor of P-gp-inhibitor/substrate status. Here, we measured the bitterness intensity of a panel of P-gp substrates and nonsubstrates with various taste sensors, and used multiple linear regression analysis to examine the relationship between P-gp-inhibitor/substrate status and various physical properties, including intensity of bitter taste measured with the taste sensor. We calculated the first principal component analysis score (PC1) as the representative value of bitterness, as all taste sensor’s outputs shared significant correlation. The P-gp substrates showed remarkably greater mean bitterness intensity than non-P-gp substrates. We found thatKmvalue of P-gp substrates were correlated with molecular weight, logP, and PC1 value, and the coefficient of determination (R2) of the linear regression equation was 0.63. This relationship might be useful as an aid to predict P-gp substrate status at an early stage of drug discovery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.