Filser Johannes Georg, Hutzler Christoph, Meischner Veronika, Veereshwarayya Vimal, Csanády György András
Institute of Toxicology, GSF-National Research Center for Environment and Health, D-85764 Neuherberg, Germany.
Chem Biol Interact. 2007 Mar 20;166(1-3):93-103. doi: 10.1016/j.cbi.2006.03.002. Epub 2006 Apr 17.
1,3-Butadiene (BD) was carcinogenic in rodents. This effect is related to reactive metabolites such as 1,2-epoxy-3-butene (EB) and especially 1,2:3,4-diepoxybutane (DEB). A third mutagenic epoxide, 3,4-epoxy-1,2-butanediol (EBD), can be formed from DEB and from 3-butene-1,2-diol (B-diol), the hydrolysis product of EB. In BD exposed rodents, only blood concentrations of EB and DEB have been published. Direct determinations of EBD and B-diol in blood are missing. In order to investigate the BD-dependent blood burden by all of these metabolites, we exposed male B6C3F1 mice and male Sprague-Dawley rats in closed chambers over 6-8h to constant atmospheric BD concentrations. BD and exhaled EB were measured in chamber atmospheres during the BD exposures. EB blood concentrations were obtained as the product of the atmospheric EB concentration at steady state with the EB blood-to-air partition coefficient. B-diol, EBD, and DEB were determined in blood collected immediately at the end of BD exposures up to 1200 ppm (B-diol, EBD) and 1280 ppm (DEB). Analysis of BD was done by GC/FID, of EB, DEB, and B-diol by GC/MS, and of EBD by LC/MS/MS. EB blood concentrations increased with BD concentrations amounting to 2.6 micromol/l (rat) and 23.5 micromol/l (mouse) at 2000 ppm BD and to 4.6 micromol/l in rats exposed to 10000 ppm BD. DEB (detection limit 0.01 micromol/l) was found only in blood of mice rising to 3.2 micromol/l at 1280 ppm BD. B-diol and EBD were quantitatively predominant in both species. B-diol increased in both species with the BD exposure concentration reaching 60 micromol/l at 1200 ppm BD. EBD reached maximum concentrations of 9.5 micromol/l at 150 ppm BD (rat) and of 42 micromol/l at 300 ppm BD (mouse). At higher BD concentrations EBD blood concentrations decreased again. This picture probably results from a competitive inhibition of the EBD producing CYP450 by BD, which occurs in both species.
1,3 - 丁二烯（BD）在啮齿动物中具有致癌性。这种效应与活性代谢产物有关，如1,2 - 环氧 - 3 - 丁烯（EB），尤其是1,2:3,4 - 二环氧丁烷（DEB）。第三种诱变环氧化物3,4 - 环氧 - 1,2 - 丁二醇（EBD）可由DEB以及EB的水解产物3 - 丁烯 - 1,2 - 二醇（B - 二醇）形成。在接触BD的啮齿动物中，仅公布了血液中EB和DEB的浓度。血液中EBD和B - 二醇的直接测定数据缺失。为了研究所有这些代谢产物导致的与BD相关的血液负荷，我们将雄性B6C3F1小鼠和雄性Sprague - Dawley大鼠置于密闭舱室中6 - 8小时，使其暴露于恒定大气BD浓度下。在BD暴露期间，测量舱室内大气中的BD和呼出的EB。EB血液浓度通过稳态时大气中EB浓度与EB血液 - 空气分配系数的乘积获得。在BD暴露结束后立即采集的血液中测定B - 二醇、EBD和DEB，BD浓度最高可达1200 ppm（B - 二醇、EBD）和1280 ppm（DEB）。BD通过气相色谱/火焰离子化检测器（GC/FID）分析，EB、DEB和B - 二醇通过气相色谱/质谱联用仪（GC/MS）分析，EBD通过液相色谱/串联质谱联用仪（LC/MS/MS）分析。EB血液浓度随BD浓度增加，在2000 ppm BD时，大鼠为2.6微摩尔/升，小鼠为23.5微摩尔/升；在暴露于10000 ppm BD的大鼠中为4.6微摩尔/升。仅在小鼠血液中发现了DEB（检测限为0.01微摩尔/升），在1280 ppm BD时升至3.2微摩尔/升。B - 二醇和EBD在两个物种中均占主导地位。两个物种中的B - 二醇均随BD暴露浓度增加，在1200 ppm BD时达到60微摩尔/升。EBD在150 ppm BD（大鼠）时达到最大浓度9.5微摩尔/升，在300 ppm BD（小鼠）时达到42微摩尔/升。在更高的BD浓度下，EBD血液浓度再次下降。这种情况可能是由于BD对产生EBD的细胞色素P450的竞争性抑制所致，这在两个物种中均会发生。
