Division of Toxicology, Wageningen University, Wageningen, The Netherlands.
Toxicol In Vitro. 2011 Feb;25(1):267-85. doi: 10.1016/j.tiv.2010.08.019. Epub 2010 Sep 7.
The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4-methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4-dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1'-oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses.
本研究基于相关组织部分体外代谢参数、体内推导的分配系数和文献中推导的生理参数，为大鼠烯丙基苯甲基丁香酚建立了基于生理学的生物动力学 (PBBK) 模型。该模型基于先前为相关烯丙基苯丁香醚建立的模型，由 8 个隔室组成，包括肝脏、肺和肾脏作为代谢隔室，以及单独的脂肪、动脉血、静脉血、富含灌注组织和灌注缓慢组织隔室。通过将 PBBK 预测的静脉隔室中甲基丁香酚浓度与文献中报道的甲基丁香酚血浆水平进行比较，通过将 PBBK 预测的剂量依赖性 2-羟基-4,5-二甲氧基丙烯基苯、3-羟基-4-甲氧基丙烯基苯和 1'-羟甲基丁香酚葡萄糖醛酸的形成百分比与文献中报道的尿液中相应代谢物排泄百分比进行比较，评估模型的预测能力。结果表明，这两种方法得到的结果在数量级上是一致的。利用所获得的模型，研究了不同口服剂量下甲基丁香酚的生物活化和解毒的相对程度。在低剂量下，形成 3-(3,4-二甲氧基苯基)-2-丙烯-1-醇和甲基丁香酚-2',3'-氧化物导致解毒，似乎是主要的代谢途径，发生在肝脏中。在高剂量下，模型揭示了肝内前致癌代谢物 1'-羟甲基丁香酚形成的相对增加。1'-羟甲基丁香酚形成的相对增加导致 1'-羟甲基丁香酚葡萄糖醛酸、1'-氧代甲基丁香酚和 1'-磺基氧甲基丁香酚形成的相对增加，后两者是甲基丁香酚的最终致癌代谢物。这些结果表明，甲基丁香酚不同代谢途径的相对重要性可能随剂量呈依赖性变化，导致高剂量下甲基丁香酚的生物活化相对增加。
