Department of Environmental Sciences and Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Toxicol Sci. 2010 Jun;115(2):322-9. doi: 10.1093/toxsci/kfq060. Epub 2010 Feb 22.
1,3-Butadiene (BD) is a known rodent and human carcinogen that is metabolized mainly by P450 2E1 to three epoxides, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol. The individual epoxides vary up to 200-fold in their mutagenic potency, with DEB being the most mutagenic metabolite. It is important to understand the internal formation of the individual epoxides to assign the relative risk for each metabolite and to understand the molecular mechanisms responsible for extensive species differences in carcinogenicity. This study presents a comprehensive exposure-response for the formation of the DEB-specific N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) in mice and rats. Using nano-ultra high pressure liquid chromatography-tandem-mass spectrometry allowed analysis of pyr-Val in mice and rats exposed to BD as low as 0.1 and 0.5 ppm BD, respectively, and demonstrated significant differences in the amounts and exposure-response of pyr-Val formation. Mice formed 10- to 60-fold more pyr-Val compared to rats at similar exposures. The formation of pyr-Val increased with exposures, and the formation was most efficient with regard to formation per parts per million BD at low exposures. While formation at higher exposures appeared linear in mice, in rats formation saturated at exposures > or = 200 ppm for 10 days. In rats, amounts of pyr-Val were lower after 20 days than after 10 days of exposure, suggesting that the lifespan of rat erythrocytes may be shortened following exposure to BD. This research supports the hypothesis that the lower susceptibility of rats to BD-induced carcinogenesis results from greatly reduced formation of DEB following exposure to BD.
1,3-丁二烯（BD）是一种已知的啮齿动物和人类致癌物，主要通过 P450 2E1 代谢为三种环氧化物，即 1,2-环氧-3-丁烯（EB）、1,2:3,4-二环氧丁烷（DEB）和 1,2-环氧-3,4-丁二醇。各个环氧化物的诱变能力差异高达 200 倍，其中 DEB 是最具诱变活性的代谢物。了解各个环氧化物的内部形成情况，对于确定每种代谢物的相对风险以及了解导致致癌性在不同物种间存在广泛差异的分子机制非常重要。本研究提供了关于 DEB 特异性 N,N-(2,3-二羟基-1,4-丁二酰基)缬氨酸（pyr-Val）在小鼠和大鼠体内形成的全面暴露-反应关系。使用纳米超高效液相色谱-串联质谱法，可以分析暴露于 BD 低至 0.1 和 0.5 ppm BD 的小鼠和大鼠中的 pyr-Val，并证明了 pyr-Val 形成的量和暴露-反应关系存在显著差异。与大鼠相比，小鼠在相似暴露量下形成的 pyr-Val 要多 10 到 60 倍。pyr-Val 的形成随着暴露量的增加而增加，并且在低暴露量下，每百万分之 BD 的形成效率最高。虽然在小鼠中形成呈线性增加，但在大鼠中，在 10 天暴露于 > = 200 ppm 的情况下，形成饱和。在大鼠中，暴露 20 天后形成的 pyr-Val 量低于暴露 10 天后形成的量，这表明大鼠红细胞的寿命可能会在暴露于 BD 后缩短。这项研究支持了这样一种假设，即大鼠对 BD 诱导的致癌作用的敏感性较低，是由于暴露于 BD 后 DEB 的形成大大减少所致。
