N-terminal globin adducts as biomarkers for formation of butadiene derived epoxides
N-terminal globin adducts as biomarkers for formation of butadiene derived epoxides
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DOI：
10.1016/j.cbi.2006.10.005
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发表时间：
2007-03-20
影响因子：
5.1
通讯作者：
Swenberg, James A.
中科院分区：
文献类型：
--
作者：
Boysen, Gunnar;Georgieva, Nadia I.;Swenberg, James A.
本文综述了丁二烯（BD）衍生的血红蛋白加合物作为丁二烯形成的环氧化物内部形成的生物标志物的最新研究进展（131）。众所周知，BD被细胞色素p450氧化成几种环氧化物，形成DNA和蛋白质加合物。1,2-环氧-3-丁烯（EB）， 1,2；3,4-二羟基丁烷（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。利用改进的Edman降解和GC-MS/MS对HB-Val和THB-Val进行分析，对物种间BD代谢产生了有价值的见解。此外，最近建立的一种pyr-Val分析方法已被证明适用于暴露于低至1 ppm的BD的啮齿动物的pyr-Val检测。这些技术已被应用于研究大鼠和雄性小鼠对BD、EB、DEB和作为EB-二醇前体的3-丁烯-1,2-二醇的广泛暴露。总之，这些数据表明，BD代谢是物种和浓度依赖的，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，特别是在低暴露下。吸入3 ppm双酚a 10天后，小鼠形成的pyr-Val是大鼠的12.5倍。相比之下，暴露于3或62.5 ppm双酚d的小鼠和大鼠中THB-Val的含量相似。此外，由于代谢激活途径饱和，小鼠和大鼠中THB-Val的形成似乎是超线性的。新陈代谢的性别差异还没有得到很好的证实。一项对雄性和雌性大鼠暴露于1000ppm双酚d 90天的研究表明，在HB-Val、pyr-Val和THB-Val的形成方面，性别差异分别为1.6倍、3.5倍和2.0倍，雌性形成环氧化物的效率更高。对BD衍生蛋白加合物的分析与观察到的BD致癌的物种和性别差异有很好的相关性，表明DEB可能确实是最重要的代谢物。(C) 2006由爱思唯尔爱尔兰有限公司出版
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 (131)). 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 I 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. (C) 2006 Published by Elsevier Ireland Ltd.