The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes, 6 Davis Drive, Research Triangle Park, NC 27709, United States.
The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes, 6 Davis Drive, Research Triangle Park, NC 27709, United States.
Toxicol Lett. 2014 Apr 21;226(2):163-72. doi: 10.1016/j.toxlet.2014.02.007. Epub 2014 Feb 18.
Acetaminophen (APAP) has been used as a probe drug to investigate drug-induced liver injury (DILI). In mice, 3'-hydroxyacetanilide (AMAP), a less-toxic isomer of APAP, has also been studied as a negative control. Various mechanisms for the divergence in toxicological response between the two isomers have been proposed. This work utilized a mechanistic, mathematical model of DILI to test the plausibility of four mechanistic hypotheses. Simulation results were compared to an array of measured endpoints in mice treated with APAP or AMAP. The four hypotheses included: (1) quantitative differences in drug metabolism profiles as a result of different affinities for the relevant enzymes; (2) differences in the amount of reactive metabolites produced due to cytochrome P450 (CYP450) inhibition by the AMAP reactive metabolites; (3) differences in the rate of conjugation between the reactive metabolites and proteins; (4) differences in the downstream effects or potencies of the reactive metabolites on vital components within hepatocytes. The simulations did not support hypotheses 3 or 4 as the most likely hypotheses underlying the difference in hepatoxic potential of APAP and AMAP. Rather, the simulations supported hypotheses 1 and 2 (less reactive metabolite produced per mole of AMAP relative to APAP). Within the simulations, the difference in reactive metabolite formation was equally likely to have occurred from differential affinities for the relevant drug metabolism enzymes or from direct CYP450 inhibition by the AMAP reactive metabolite. The demonstrated method of using simulation tools to probe the importance of possible contributors to toxicological observations is generally applicable across species.
对乙酰氨基酚（APAP）已被用作研究药物性肝损伤（DILI）的探针药物。在小鼠中，3'-羟基乙酰苯胺（AMAP），APAP 的一种毒性较低的异构体，也被用作阴性对照进行了研究。人们提出了各种机制来解释这两种异构体在毒性反应上的差异。本研究利用 DILI 的机制数学模型来检验四种机制假说的合理性。将模拟结果与用 APAP 或 AMAP 处理的小鼠的一系列测量终点进行比较。这四个假设包括：（1）由于与相关酶的亲和力不同，导致药物代谢谱的定量差异；（2）由于 AMAP 反应性代谢物对细胞色素 P450（CYP450）的抑制作用，导致产生的反应性代谢物数量不同；（3）反应性代谢物与蛋白质之间的结合速率差异；（4）反应性代谢物对肝细胞内重要成分的下游影响或效力差异。模拟结果不支持假说 3 或 4，因为这两个假说都不是导致 APAP 和 AMAP 肝毒性潜力差异的最可能假说。相反，模拟结果支持假说 1 和 2（与 APAP 相比，每摩尔 AMAP 产生的反应性代谢物较少）。在模拟中，反应性代谢物形成的差异可能同样是由于对相关药物代谢酶的亲和力不同，或者是由于 AMAP 反应性代谢物对 CYP450 的直接抑制所致。该研究证明了使用模拟工具来探究可能导致毒理学观察结果的重要因素的方法在跨物种中具有普遍适用性。
