Elfarra A A, Krause R J, Kemper R A
Department of Comparative Biosciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive West, Madison, WI 53706-1102, USA.
Chem Biol Interact. 2001 Jun 1;135-136:239-48. doi: 10.1016/s0009-2797(01)00193-4.
Species differences in 1,3-butadiene (BD) bioactivation and detoxication have been implicated in the greater sensitivity of mice to the carcinogenic effects of BD compared to rats, but the molecular basis for species differences in BD metabolism is not well understood. Previous and recent work conducted in this laboratory has examined the relative rates of BD oxidation to epoxybutene (EB) in male and female B6C3F1 mouse tissues, characterized the major cytochrome P450 enzymes involved in BD bioactivation in these tissues, and determined the potential utility of the freshly isolated hepatocyte model to investigate species differences in metabolism of BD and related compounds. Collectively, the results suggest a role for P450s 2E1, 2A5, and 4B1 in sex and tissue differences in BD bioactivation in the mouse. When coordinated metabolism of EB was investigated in male B6C3F1 mouse and Sprague-Dawley rat hepatocytes, the hepatocytes from both species were found to catalyze EB oxidation to meso- and (+/-)-diepoxybutane (DEB), EB hydrolysis to 3-butene-1,2-diol (BDD), and EB conjugation to form GSH conjugates (GSEB). The metabolite area under the curve (AUC) exhibited dependence on the EB concentration used. However, the EB activation/detoxication ratios with the mouse hepatocytes were much higher than the ratios obtained with the rat hepatocytes. These results illustrate the potential utility of the hepatocyte model for estimating flux through competing metabolic pathways and predicting in-vivo metabolism of EB. Collectively, the results may allow a better understanding of the molecular and kinetic basis of species differences in BD metabolism and may lead to a more accurate assessment of human risk.
1,3 - 丁二烯（BD）生物活化和解毒过程中的物种差异被认为是小鼠相较于大鼠对BD致癌作用更为敏感的原因，但BD代谢中物种差异的分子基础尚未得到很好的理解。本实验室之前和最近开展的工作研究了雄性和雌性B6C3F1小鼠组织中BD氧化为环氧丁烯（EB）的相对速率，鉴定了这些组织中参与BD生物活化的主要细胞色素P450酶，并确定了新鲜分离的肝细胞模型在研究BD及相关化合物代谢物种差异方面的潜在效用。总体而言，结果表明细胞色素P450 2E1、2A5和4B1在小鼠BD生物活化的性别和组织差异中发挥作用。当研究雄性B6C3F1小鼠和Sprague - Dawley大鼠肝细胞中EB的协同代谢时，发现两个物种的肝细胞均能催化EB氧化为内消旋和（±）-二环氧丁烷（DEB），EB水解为3 - 丁烯 - 1,2 - 二醇（BDD），以及EB结合形成谷胱甘肽结合物（GSEB）。代谢物曲线下面积（AUC）表现出对所用EB浓度的依赖性。然而，小鼠肝细胞的EB活化/解毒比率远高于大鼠肝细胞获得的比率。这些结果说明了肝细胞模型在估计通过竞争性代谢途径的通量以及预测EB体内代谢方面的潜在效用。总体而言，这些结果可能有助于更好地理解BD代谢中物种差异的分子和动力学基础，并可能导致对人类风险进行更准确的评估。
