The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model.
The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model.
复制标题
DOI：
10.1186/1742-4682-9-55
复制
发表时间：
2012-12-19
影响因子：
--
通讯作者：
Nijhout HF
中科院分区：
文献类型：
--
作者：
Ben-Shachar R;Chen Y;Luo S;Hartman C;Reed M;Nijhout HF
对乙酰氨基酚（N-乙酰基-对氨基苯酚）是世界上使用最广泛的非处方或处方止痛药。对乙酰氨基酚在肝脏中代谢，产生有毒副产物，可通过与谷胱甘肽结合而去除。对乙酰氨基酚过量，无论是意外还是故意的，都是美国急性肝衰竭的主要原因，每年有56，000例急诊室就诊。过量的标准治疗方法是N-乙酰半胱氨酸（NAC），用于刺激谷胱甘肽的产生。我们建立了一个对乙酰氨基酚转运和代谢的数学模型，包括以下部分：肠道，血浆，肝脏，组织，尿液。在肝室中，对乙酰氨基酚的代谢包括硫酸化、葡萄糖醛酸化、与谷胱甘肽结合、产生毒性代谢产物和肝损伤，尽可能从文献中获取生化参数。然后将该模型连接到先前构建的谷胱甘肽代谢模型。我们表明，我们的模型准确地再现了已发表的临床和实验数据的剂量依赖性时间过程中的对乙酰氨基酚在血浆中，对乙酰氨基酚及其代谢产物在尿液中的积累，以及与有毒产品的共轭引起的谷胱甘肽的消耗。我们使用该模型来研究过量或长期使用治疗剂量引起的肝损伤程度，以及葡萄糖醛酸化酶多态性的影响。我们使用该模型来研究谷胱甘肽的消耗以及作为解毒剂给予的N-乙酰半胱氨酸剂量的大小和时间的影响。我们的模型根据APAP过量的大小和治疗时间准确预测患者死亡或康复。该数学模型为研究不同剂量对乙酰氨基酚对肝脏对乙酰氨基酚和谷胱甘肽代谢的影响提供了新的工具。它可用于研究对乙酰氨基酚的代谢如何取决于肝酶的表达水平。最后，它可用于预测患者对APAP剂量和不同NAC给药策略的代谢和生理反应。
Acetaminophen (N-acetyl-para-aminophenol) is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC), which is given to stimulate the production of glutathione. We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism. We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment. The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and glutathione. It can be used to study how the metabolism of acetaminophen depends on the expression level of liver enzymes. Finally, it can be used to predict patient metabolic and physiological responses to APAP doses and different NAC dosing strategies.
登录
查看更多内容
影响因子：
3
作者：
Krenzelok, Edward P.;Royal, Mike A.
通讯作者：
Royal, Mike A.
影响因子：
4.1
作者：
HARVISON, PJ;GUENGERICH, FP;NELSON, SD
通讯作者：
NELSON, SD
DOI：
10.1111/j.1365-2710.2004.00626.x
发表时间：
2005-04-01
影响因子：
2
作者：
Critchley, JAJH;Critchley, LAH;Tomlinson, B
通讯作者：
Tomlinson, B
DOI：
10.1016/s0731-7085(03)00573-9
发表时间：
2004-02-18
影响因子：
3.4
作者：
Jensen, LS;Valentine, J;Evans, AM
通讯作者：
Evans, AM
影响因子：
3.3
作者：
Court, MH;Greenblatt, DJ
通讯作者：
Greenblatt, DJ