Institute of Toxicology, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85764 Neuherberg, Germany.
Toxicol Sci. 2010 Mar;114(1):25-37. doi: 10.1093/toxsci/kfp297. Epub 2009 Dec 9.
The industrial chemical 1,3-butadiene (BD) is a potent carcinogen in mice and a weak one in rats. This difference is generally related to species-specific burdens by the metabolites 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD), which are all formed in the liver. Only limited data exist on BD metabolism in the rodent liver. Therefore, metabolism of BD, its epoxides, and the intermediate 3-butene-1,2-diol (B-diol) was studied in once-through perfused livers of male B6C3F1 mice and Sprague-Dawley rats. In BD perfusions, predominantly EB and B-diol were found (both species). DEB and EBD were additionally detected in mouse livers. Metabolism of BD showed saturation kinetics (both species). In EB perfusions, B-diol, EBD, and DEB were formed with B-diol being the major metabolite. Net formation of DEB was larger in mouse than in rat livers. In both species, hepatic clearance (Cl(H)) of EB was slightly smaller than the perfusion flow. In DEB perfusions, EBD was formed as a major metabolite. Cl(H) of DEB was 61% (mouse) and 73% (rat) of the perfusion flow. In the B-diol-perfused rat liver, EBD was formed as a minor metabolite. Cl(H) of B-diol was 53% (mouse) and 34% (rat) of the perfusion flow. In EBD-perfused rat livers, Cl(H) of EBD represented only 22% of the perfusion flow. There is evidence for qualitative species differences with regard to the enzymes involved in BD metabolism. The first quantitative findings in whole livers showing intrahepatic first-pass metabolism of BD and EB metabolites will improve the risk estimation of BD.
1,3-丁二烯（BD）是一种具有潜在致癌性的工业化学物质，对小鼠具有较强的致癌性，而对大鼠的致癌性较弱。这种差异通常与代谢物 1,2-环氧-3-丁烯（EB）、1,2:3,4-二环氧丁烷（DEB）和 3,4-环氧-1,2-丁二醇（EBD）的物种特异性负担有关，这些代谢物均在肝脏中形成。目前关于啮齿动物肝脏中 BD 代谢的相关数据有限。因此，我们对雄性 B6C3F1 小鼠和 Sprague-Dawley 大鼠一次性灌注肝脏中的 BD、其环氧化物以及中间产物 3-丁烯-1,2-二醇（B-diol）的代谢情况进行了研究。在 BD 灌注实验中，我们发现两种物种均主要生成 EB 和 B-diol，而 DEB 和 EBD 仅在小鼠肝脏中被检测到。BD 的代谢呈现饱和动力学特征（两种物种均如此）。在 EB 灌注实验中，形成了 B-diol、EBD 和 DEB，其中 B-diol 是主要代谢产物。在小鼠肝脏中，DEB 的净生成量大于大鼠肝脏。在两种物种中，EB 的肝清除率（Cl(H)）略小于灌注流速。在 DEB 灌注实验中，EBD 是主要的代谢产物。DEB 的 Cl(H)为灌注流速的 61%（小鼠）和 73%（大鼠）。在 B-diol 灌注的大鼠肝脏中，EBD 是次要代谢产物。B-diol 的 Cl(H)为灌注流速的 53%（小鼠）和 34%（大鼠）。在 EBD 灌注的大鼠肝脏中，EBD 的 Cl(H)仅占灌注流速的 22%。这些结果提示我们，BD 代谢中涉及的酶可能存在定性的物种差异。本研究首次在整个肝脏中定量发现了 BD 和 EB 代谢物的肝内首过代谢，这将有助于提高 BD 的风险评估水平。
