Department of Environmental and Occupational Health and The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Toxicol Sci. 2012 Jan;125(1):30-40. doi: 10.1093/toxsci/kfr272. Epub 2011 Oct 14.
1,3-Butadiene (BD) is an important industrial chemical that is classified as a human carcinogen. BD carcinogenicity has been attributed to its metabolism to several reactive epoxide metabolites and formation of the highly mutagenic 1,2:3,4-diepoxybutane (DEB) has been hypothesized to drive mutagenesis and carcinogenesis at exposures experienced in humans. We report herein the formation of DEB-specific N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) in BD-exposed workers as a biomarker of DEB formation. pyr-Val was determined in BD monomer and polymer plant workers that had been previously analyzed for several other biomarkers of exposure and effect. pyr-Val was detected in 68 of 81 (84%) samples ranging from 0.08 to 0.86 pmol/g globin. Surprisingly, pyr-Val was observed in 19 of 23 administrative control subjects not known to be exposed to BD, suggesting exposure from environmental sources of BD. The mean ± SD amounts of pyr-Val were 0.11 ± 0.07, 0.16 ± 0.12, and 0.29 ± 0.20 pmol/g globin in the controls, monomer, and polymer workers, respectively, clearly demonstrating formation of DEB in humans. The amounts of pyr-Val found in this study suggest that humans are much less efficient in the formation of DEB than mice or rats at similar exposures. Formation of pyr-Val was more than 50-fold lower than has been associated with increased mutagenesis in rodents. The results further suggest that formation of DEB relative to other epoxides is significantly different in the highest exposed polymer workers compared with controls and BD monomer workers. Whether this is due to saturation of metabolic formation or increased GST-mediated detoxification could not be determined.
1,3-丁二烯（BD）是一种重要的工业化学品，被归类为人类致癌物。BD 的致癌性归因于其代谢为几种活性环氧化物代谢物，并且形成高度致突变的 1,2:3,4-二环氧丁烷（DEB）已被假设为驱动在人类暴露于其中的致突变和致癌作用。我们在此报告了作为 DEB 形成生物标志物的在 BD 暴露工人中 DEB 特异性 N,N-（2,3-二羟基-1,4-丁二酰）缬氨酸（pyr-Val）的形成。在先前已经分析了几种其他暴露和效应生物标志物的 BD 单体和聚合物工厂工人中测定了 pyr-Val。在 81 个样本中的 68 个（84％）中检测到 pyr-Val，范围从 0.08 到 0.86 pmol/g 球蛋白。令人惊讶的是，在 19 个行政对照受试者中观察到了 pyr-Val，这些受试者不知道暴露于 BD，表明来自 BD 的环境来源的暴露。在对照、单体和聚合物工人中，pyr-Val 的平均值±SD 分别为 0.11±0.07、0.16±0.12 和 0.29±0.20 pmol/g 球蛋白，清楚地表明 DEB 在人体中的形成。在这项研究中发现的 pyr-Val 量表明，在类似暴露下，人类形成 DEB 的效率远低于小鼠或大鼠。与啮齿动物中的致突变性增加相关的 pyr-Val 形成量低 50 倍以上。结果还表明，与对照和 BD 单体工人相比，最高暴露的聚合物工人中 DEB 的形成与其他环氧化物相比明显不同。这是否是由于代谢形成的饱和或 GST 介导的解毒作用增加所致，尚无法确定。
