Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol.
Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol.
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暴露于 3-丁烯-1,2-二醇的啮齿类动物中 3,4-环氧-1,2-丁二醇的 DNA 和血红蛋白加合物的定量。
DOI：
10.1093/carcin/bgi119
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发表时间：
2005
期刊：
影响因子：
4.7
通讯作者：
Swenberg,JA
中科院分区：
文献类型：
--
作者：
Powley,MW;Li,Y;Upton,PB;Walker,VE;Swenberg,JA
1，3-丁二醇（BD）是一种已确认的啮齿动物致癌物，也是一种可疑的人类致癌物，在生物转化过程中形成致突变的环氧化物代谢物。个体DNA活性中间体在BD致突变性和致癌性中的作用的种属差异尚未完全了解。有证据表明，1，2：3，4-二环氧丁烷（DEB）是小鼠暴露于低浓度BD诱导的致突变效应的原因，3-丁烯-1，2-二醇（BD-二醇）的代谢产物参与了小鼠和大鼠高浓度暴露的致突变性。在BD-二醇的生物转化过程中形成了两种反应性代谢产物3，4-环氧-1，2-丁二醇（EB-二醇）和羟甲基乙烯基酮（HMVK），可能参与BD-二醇相关的致突变性。为了检查EB-二醇在BD-二醇致突变性中的作用，我们评价了通过吸入暴露于0、6、18和36 p. p.m. BD-二醇4周（6 h/天× 5天/周）的雌性B6 C3 F1小鼠和雌性F344大鼠中N7-（2，3，4-三羟基丁基）鸟嘌呤（THB-Gua）和N-（2，3，4-三羟基丁基）缬氨酸（THB-Val）的剂量测定。结果显示小鼠中THB-Gua和THB-Val的水平均高于大鼠。THB-瓜加合物的评价显示，两种物种的肝脏和肺之间几乎没有差异，表明EB-二醇是稳定的，可以自由循环。数据还表明，THB加合物的形成在两个物种中在下午18点左右开始达到平台。最重要的是，THB加合物形成的剂量-反应曲线的形状模仿了次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（Hprt）突变频率。这表明，THB加合物（被认为不是导致突变的原因）是暴露于BD-二醇的啮齿动物致突变性的良好定量指标。尽管仍需评价HMVK的潜在作用，但数据表明EB-二醇至少部分负责啮齿动物中BD-二醇相关的致突变性。
1,3-Butadiene (BD) is a confirmed rodent carcinogen and a suspect human carcinogen that forms mutagenic epoxide metabolites during biotransformation. Species differences in the roles of individual DNA reactive intermediates in BD mutagenicity and carcinogenicity are not completely understood. Evidence suggests that 1,2:3,4-diepoxybutane (DEB) is responsible for the mutagenic effect induced by exposures to low concentrations of BD in mice and that metabolites of 3-butene-1,2-diol (BD-diol) are involved in the mutagenicity at high exposures in both mice and rats. Two reactive metabolites, 3,4-epoxy-1,2-butanediol (EB-diol) and hydroxymethylvinyl ketone (HMVK), are formed during the biotransformation of BD-diol and could potentially be involved in BD-diol associated mutagenicity. To examine the role of EB-diol in BD-diol mutagenicity we have evaluated the dosimetry ofN7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) andN-(2,3,4-trihydroxybutyl)valine (THB-Val) in female B6C3F1 mice and female F344 rats exposed by inhalation to 0, 6, 18 and 36 p.p.m. BD-diol for 4 weeks (6 h/day × 5 days/week). Results showed higher levels of both THB-Gua and THB-Val in mice than in rats. An evaluation of THB-Gua adducts showed virtually no differences between liver and lung for either species, suggesting that EB-diol is stable and is freely circulated. The data also indicated that THB adduct formation began to plateau around 18 p.p.m. in both species. Most importantly, the shape of the dose–response curve for THB adduct formation mimicked the one observed for hypoxanthine-guanine phosphoribosyltransferase (Hprt)mutation frequency. This showed that THB adducts, which are not thought to be responsible for causing the mutations, are good quantitative indicators of mutagenicity in rodents exposed to BD-diol. Although the potential contribution of HMVK still needs to be evaluated, the data suggest that EB-diol is responsible, at least in part, for BD-diol associated mutagenicity in rodents.