Yu Rong Chun, Hattis Dale, Landaw Elliot M, Froines John R
Center for Occupational and Environmental Health, UCLA School of Public Health, Los Angeles, CA 90095, USA.
Arch Toxicol. 2002 Jan;75(11-12):643-52. doi: 10.1007/s00204-001-0298-2.
Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.
同时接触甲乙酮（MEK）会增强正己烷对人类和动物的神经毒性。这种效应与血液中2,5 - 己二酮（2,5 - HD）的持久性增加有关，这可能是由于MEK抑制了2,5 - HD的Ⅱ相生物转化。以前没有定量的毒代动力学模型来描述这种相互作用。在本研究中，我们构建了一个毒代动力学模型来描述MEK对2,5 - HD代谢和消除的抑制作用。利用一项已发表研究中大鼠2,5 - HD血药浓度的实验数据来估计模型参数。评估了三种不同的抑制机制：竞争性抑制、非竞争性抑制和反竞争性抑制。从高剂量外推至低剂量以评估在实验条件之外MEK对2,5 - HD的相互作用效应。所建立的模型成功地描述了MEK抑制时2,5 - HD的毒代动力学行为。与非竞争性和反竞争性模型（分别为403和440 mg/l）相比，竞争性抑制模型得出的MEK对2,5 - HD抑制常数（65.5 mg/l）的估计值要低得多。2,5 - HD的表观半衰期似乎是米氏常数以及大鼠体内2,5 - HD和MEK浓度的线性函数。大鼠血液中2,5 - HD的曲线下面积是血液中2,5 - HD和MEK浓度的非线性函数。本研究强调了MEK对2,5 - HD失活和消除的相互作用效应的重要性，并进一步说明了毒代动力学建模在研究与多种化学物质接触相关的化学相互作用方面的优势。
