Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene
Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene
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DOI：
10.1021/tx980265f
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发表时间：
1999-07-01
影响因子：
4.1
通讯作者：
Swenberg, JA
中科院分区：
文献类型：
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作者：
Koc, H;Tretyakova, NY;Swenberg, JA
1,3-丁二烯 (BD) 是一种大批量化学品，用于生产橡胶和塑料。 ED 对小鼠是一种强效致癌物，对大鼠来说是一种较弱的致癌物，并且已被列为可能的人类致癌物。在体内代谢激活后，它形成 DNA 反应性代谢物：1,2-环氧-3-丁烯 (EB)、1,2:3,4-二环氧丁烷 (DEB) 和 3,4-环氧-1,2-丁二醇 (EBD)。研究了暴露于 0、20、62.5 或 625 ppm BD 的 B6C3F1 小鼠和 F344 大鼠的肝脏、肺和肾脏中 ED 的这些代谢物形成的 N-7 鸟嘌呤加合物的分子剂量测定。通过中性热水解从 DNA 中分离出 N-7-(2,3,4-三羟基丁-1-基)-鸟嘌呤 (THB-Gua)、N-7-(2-羟基-3-丁烯-1-基)鸟嘌呤 (EB-Gua I) 和 N-7-(1-羟基-3-丁烯-2-基)鸟嘌呤 (EB-Gua II) 的加合物、外消旋形式和内消旋形式，并在固相萃取中脱盐柱，并通过 LC/ESI+/MS/MS 进行定量。对于给定加合物，小鼠中每 10(6) 个正常鸟嘌呤碱基的加合物数量高于暴露于 625 ppm ED 的大鼠，但在较低暴露水平下通常相似。 THB-Gua 加合物最为丰富（比 EB-Gua 高 6-27 倍），并表现出非线性的暴露-反应关系。在大鼠中，THB-Gua 加合物形成的暴露-反应曲线在 62.5 ppm 后达到平台，表明代谢激活饱和。在 62.5 至 625 ppm ED 之间，小鼠中 THB-Gua 加合物的数量持续增加。相比之下，不太常见的 EB-Gua 加合物在两个物种中都具有线性暴露-反应关系。结合本研究的信息和之前关于 ED 代谢的数据，我们能够估计由 DEB 和 EBD 产生的 THB-Gua 的数量，并得出结论，大部分 THB-Gua 是由 EBD 形成的。我们假设大部分 EBD 是由 DEB 在内质网内立即转化为 EBD 产生的。这项研究强调需要测量大鼠和小鼠组织中的 EBD 水平，以及开发可与 DNA 结合的独特 DEB 生物标记物。
1,3-Butadiene (BD) is a high-volume chemical used in the production of rubber and plastic. ED is a potent carcinogen in mice and a much weaker carcinogen in rats, and has been classified as a probable human carcinogen. Upon metabolic activation in vivo, it forms DNA-reactive metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD). The molecular dosimetry of N-7 guanine adduct formation by these metabolites of ED in liver, lung, and kidney of B6C3F1 mice and F344 rats exposed to 0, 20, 62.5, or 625 ppm BD was studied. The adducts, racemic and meso forms of N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua), N-7-(2-hydroxy-3-buten-1-yl)guanine (EB-Gua I), and N-7-(1-hydroxy-3-buten-2-yl)guanine (EB-Gua II), were isolated from DNA by neutral thermal hydrolysis, desalted on solid-phase extraction cartridges, and quantitated by LC/ESI+/MS/MS. The number of adducts per 10(6) normal guanine bases for a given adduct was higher in mice than rats exposed to 625 ppm ED, but generally similar at lower levels of exposure. The THB-Gua adducts were the most abundant (6-27 times higher than EB-Gua) and exhibited a nonlinear exposure-response relationship. In rats, the exposure-response curves for the formation of THB-Gua adducts reached a plateau after 62.5 ppm, suggesting saturation of metabolic activation. The number of THB-Gua adducts continued to increase in mice between 62.5 and 625 ppm ED. In contrast, the less common EB-Gua adducts had a linear exposure-response relationship in both species. Combining the information from this study with previous data on ED metabolism, we were able to estimate the number of THB-Gua that resulted from DEB and EBD, and conclude that most of the THB-Gua is formed from EBD. We hypothesize that most of the EBD arises from the immediate conversion of DEB to EBD within the endoplasmic reticulum. This study highlights the need for measurements of the levels of EBD in tissues of rats and mice and for the development of a unique biomarker for DEB that is available for binding to DNA.