Boysen Gunnar, Georgieva Nadia I, Upton Patricia B, Walker Vernon E, Swenberg James A
Department of Environmental Sciences and Engineering, The University of North Carolina, Chapel Hill, NC 27599-7431, USA.
Chem Biol Interact. 2007 Mar 20;166(1-3):84-92. doi: 10.1016/j.cbi.2006.10.005. Epub 2006 Nov 7.
The aim of this review is to summarize our recent data on butadiene (BD) derived hemoglobin adducts as biomarkers for the internal formation of the individual epoxides formed by butadiene (BD). It is well known that BD is oxidized by cytochrome P450s to several epoxides that form DNA and protein adducts. 1,2-Epoxy-3-butene (EB), 1,2;3,4-diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol) form N-(2-hydroxy-3-butenyl)-valine (HB-Val), N,N-(2,3-dihydroxy-1,4-butadiyl)-valine (pyr-Val) and N-(2,3,4-trihydroxybutyl)-valine (THB-Val) adducts, respectively. The analysis of HB-Val and THB-Val by the modified Edman degradation and GC-MS/MS has generated valuable insights into BD metabolism across species. In addition, a recently established method for the analysis of pyr-Val has been proven to be suitable for detection of pyr-Val in rodents exposed to BD as low as 1 ppm. These technologies have been applied to study a wide range of exposures to BD, EB, DEB, and 3-butene-1,2-diol as a precursor of EB-diol in male and female mice and rats. Altogether the data have shown that BD metabolism is species and concentration dependent, consistent with metabolism and carcinogenesis data. Mice form much more HB-Val and pyr-Val than rats, especially at low exposures. After 10 days of inhalation exposure to 3 ppm BD, mice formed 12.5-fold more pyr-Val than rats. In contrast, the amounts of THB-Val were similar in mice and rats exposed to 3 or 62.5 ppm BD. Furthermore, it appears that the formation of THB-Val is supralinear in mice and rats due to saturation of metabolic activation pathways. Gender differences in metabolism are less well established. One study with male and female rats exposed to 1000 ppm BD for 90 days demonstrated a 1.6-, 3.5- and 2.0-fold gender difference in formation of HB-Val, pyr-Val and THB-Val, respectively, with females being more efficient in epoxide formation. The analyses of BD derived protein adducts correlate well with the observed species and gender differences in BD-carcinogenesis and suggest that DEB may indeed be the most important metabolite.
本综述的目的是总结我们最近关于丁二烯（BD）衍生的血红蛋白加合物的数据，这些加合物可作为丁二烯（BD）形成的单个环氧化物在体内形成的生物标志物。众所周知，BD可被细胞色素P450氧化为几种环氧化物，这些环氧化物会形成DNA和蛋白质加合物。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（EB-二醇）分别形成N-（2-羟基-3-丁烯基）-缬氨酸（HB-Val）、N,N-（2,3-二羟基-1,4-丁二基）-缬氨酸（pyr-Val）和N-（2,3,4-三羟基丁基）-缬氨酸（THB-Val）加合物。通过改良的埃德曼降解法和气相色谱-串联质谱法对HB-Val和THB-Val进行分析，为跨物种的BD代谢提供了有价值的见解。此外，最近建立的一种分析pyr-Val的方法已被证明适用于检测暴露于低至1 ppm BD的啮齿动物体内的pyr-Val。这些技术已被应用于研究雄性和雌性小鼠及大鼠对BD、EB、DEB和作为EB-二醇前体的3-丁烯-1,2-二醇的广泛暴露情况。总体数据表明，BD代谢具有物种和浓度依赖性，这与代谢和致癌数据一致。小鼠比大鼠形成更多的HB-Val和pyr-Val，尤其是在低暴露水平下。吸入3 ppm BD 10天后，小鼠形成的pyr-Val比大鼠多12.5倍。相比之下，暴露于3或62.5 ppm BD的小鼠和大鼠体内THB-Val的量相似。此外，由于代谢激活途径的饱和，小鼠和大鼠体内THB-Val的形成似乎呈超线性。代谢的性别差异尚不明确。一项对雄性和雌性大鼠暴露于1000 ppm BD 90天的研究表明，在HB-Val、pyr-Val和THB-Val的形成上，性别差异分别为1.6倍、3.5倍和2.0倍，雌性在环氧化物形成方面更高效。对BD衍生的蛋白质加合物的分析与观察到的BD致癌过程中的物种和性别差异密切相关，并表明DEB可能确实是最重要的代谢产物。
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