DataSheet1_Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model.pdf

The liver metabolizes a variety of substances that sometimes interact and regulate each other. The modeling of a single cell or a single metabolic pathway does not represent the complexity of the organ, including metabolic zonation (heterogeneity of functions) along with liver sinusoids. Here, we integrated multiple metabolic pathways into a single numerical liver zonation model, including drug and glucose metabolism. The model simulated the time-course of metabolite concentrations by the combination of dynamic simulation and metabolic flux analysis and successfully reproduced metabolic zonation and localized hepatotoxicity induced by acetaminophen (APAP). Drug metabolism was affected by nutritional status as the glucuronidation reaction rate changed. Moreover, sensitivity analysis suggested that the reported metabolic characteristics of obese adults and healthy infants in glucose metabolism could be associated with the metabolic features of those in drug metabolism. High activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate phosphatase in obese adults led to increased APAP oxidation by cytochrome P450 2E1. In contrast, the high activity of glycogen synthase and low activities of PEPCK and glycogen phosphorylase in healthy infants led to low glucuronidation and high sulfation rates of APAP. In summary, this model showed the effects of glucose metabolism on drug metabolism by integrating multiple pathways into a single liver metabolic zonation model.

肝脏对多种物质进行代谢，这些物质有时相互作用并相互调节。单个细胞或单一代谢途径的建模并不能代表器官的复杂性，包括肝脏窦状隙（功能异质性）的代谢区域。在此，我们将多个代谢途径整合为一个统一的数值化肝脏代谢区域模型，其中包括药物和葡萄糖代谢。该模型通过动态模拟和代谢通量分析的结合，模拟了代谢物浓度的时程变化，并成功再现了由对乙酰氨基酚（APAP）引起的代谢区域化和局部肝毒性。药物代谢受到营养状况的影响，因为葡萄糖醛酸化反应速率发生了变化。此外，敏感性分析表明，肥胖成年人和健康婴儿在葡萄糖代谢中报道的代谢特征可能与药物代谢中的代谢特征相关。肥胖成年人体内磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸磷酸酶的高活性导致细胞色素P450 2E1对APAP的氧化增加。相反，健康婴儿体内糖原合成酶的高活性和PEPCK以及糖原磷酸化酶的低活性导致APAP的低葡萄糖醛酸化和高硫酸化率。总之，该模型通过将多个途径整合到一个肝脏代谢区域模型中，展示了葡萄糖代谢对药物代谢的影响。