Kohn M C, Melnick R L
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Carcinogenesis. 1993 Apr;14(4):619-28. doi: 10.1093/carcin/14.4.619.
Inhaled 1,3-butadiene, a monomer used in the production of synthetic rubber and other resins, is metabolized to mutagenic and carcinogenic epoxide intermediates. A physiologically based pharmacokinetic model of the uptake, tissue distribution, and metabolism of butadiene was constructed to determine if the biochemical kinetic constants obtained from in vitro studies are consistent with the observed in vivo uptake and metabolism. The model includes compartments for lung, blood, fat, liver, other rapidly perfused tissues ('viscera') and slowly perfused tissues. Metabolism of butadiene was assumed to occur in viscera in addition to lung and liver. Enzymatic reaction rate equations for the formation of 1,2-epoxy-3-butene, for hydrolysis of this epoxide, and for its conjugation with glutathione were also included. Physiological and biochemical parameters for the mouse, rat and human were obtained from the literature; they were not adjusted to produce a fit to experimental data. The model was used to test the hypothesis that differences in uptake and clearance of butadiene by the three species are due to differences in the activities of the metabolizing enzymes. The model reproduces whole-body observations for the mouse and rat. It predicts that inhalation uptake of butadiene and formation and retention of epoxybutene are controlled to a much greater extent by physiological parameters than by biochemical parameters and that storage in the fat represents a significant fraction of the retained butadiene. Accumulation of epoxybutene in the blood is predicted to be higher in mice than in rats or humans, but accumulation of the epoxide intermediate in the liver is predicted to be highest in humans. The epoxide tissue concentrations predicted by the model do not, by themselves, correlate with tumor incidence in mice and rats, indicating that other factors are crucial for carcinogenesis induced by butadiene.
吸入的1,3 - 丁二烯是一种用于生产合成橡胶和其他树脂的单体，它会代谢为具有致突变性和致癌性的环氧化合物中间体。构建了一个基于生理学的丁二烯摄取、组织分布和代谢的药代动力学模型，以确定从体外研究获得的生化动力学常数是否与体内观察到的摄取和代谢一致。该模型包括肺、血液、脂肪、肝脏、其他快速灌注组织（“内脏”）和缓慢灌注组织的隔室。假定丁二烯除了在肺和肝脏中代谢外，还在内脏中发生代谢。还包括了1,2 - 环氧 - 3 - 丁烯形成、该环氧化物水解及其与谷胱甘肽结合的酶促反应速率方程。从小鼠、大鼠和人类的文献中获取了生理学和生化参数；未对这些参数进行调整以使其与实验数据拟合。该模型用于检验以下假设：三种物种对丁二烯摄取和清除的差异是由于代谢酶活性的差异所致。该模型重现了小鼠和大鼠的全身观测结果。它预测，丁二烯的吸入摄取以及环氧丁烯的形成和滞留，在很大程度上受生理参数而非生化参数的控制，并且脂肪中的储存占保留丁二烯的很大一部分。预计小鼠血液中环氧丁烯的积累高于大鼠或人类，但预计该环氧化合物中间体在肝脏中的积累在人类中最高。该模型预测的环氧化物组织浓度本身与小鼠和大鼠的肿瘤发生率无关，这表明其他因素对于丁二烯诱导的致癌作用至关重要。
