Oe T, Kambouris S J, Walker V E, Meng Q, Recio L, Wherli S, Chaudhary A K, Blair I A
Center for Cancer Pharmacology, University of Pennsylvania, 302 D Abramson Research Building, Civic Center Boulevard and Osler Circle, Philadelphia, Pennsylvania 19104-4318,USA.
Chem Res Toxicol. 1999 Mar;12(3):247-57. doi: 10.1021/tx980193s.
Liquid chromatography (LC) in combination with tandem mass spectrometry (MS/MS) and stable isotope methodology was employed for the analysis of the N7-guanine (Gua) adducts derived from 1,2:3, 4-diepoxybutane (BDO2) a reactive metabolite of 1,3-butadiene (BD). Two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)guanine (THBG) were identified in the livers of both mice and rats. One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2. There was significantly more (+/-)-THBG and meso-THBG in the liver DNA of the mice when compared with those of the rats during the 10 days of exposure to BD and the 6 days of postexposure that were monitored. There was a 2-fold excess of (+/-)-THBG over meso-THBG in the rat liver at all the time points. In the mouse liver after 10 days of exposure to BD, the (+/-)-THBG (3.9 adducts/10(6) normal bases) was also present in an almost 2-fold excess over meso-THBG (2.2 adducts/10(6) normal bases). However, 6-days after exposure to BD, (+/-)-THBG (1.2 adducts/10(6) normal bases) and meso-THBG (1.0 adduct/10(6) normal bases) were present in almost equal amounts in the mouse liver. Furthermore, there was an almost 5-fold excess of the two THBG diastereomers in the mouse liver DNA 6 days after exposure to BD when compared with rat liver DNA. The half-lives of (+/-)-THBG and meso-THBG appeared to be slightly longer in mouse liver (4.1 and 5.5 days, respectively) than in rat liver (3.6 and 4.0 days, respectively). The apparent persistence of these adducts in the mouse may contribute to the increased susceptibility of this species to BD-induced carcinogenesis. It is possible that (+/-)-THBG and meso-THBG could have also been derived from the reaction of DNA with the hydrolysis product of BDO2, 1,2-dihydroxy-3,4-epoxybutane (DHEB). Surprisingly, a vast majority of the studies in which the mutagenic and carcinogenic potential of BDO2 have been examined have only employed the commercially available (+/-)-BDO2. In light of the present findings, additional studies will be required to determine the potency of meso-BDO2 and the DHEB that is the precursor to meso-THBG as mutagens and carcinogens.
采用液相色谱（LC）结合串联质谱（MS/MS）和稳定同位素方法，对1,3 - 丁二烯（BD）的活性代谢物1,2:3,4 - 二环氧丁烷（BDO2）衍生的N7 - 鸟嘌呤（Gua）加合物进行分析。在小鼠和大鼠的肝脏中均鉴定出两种非对映异构体形式的N7 - （2,3,4 - 三羟基丁基）鸟嘌呤（THBG）。其中一种非对映异构体[（+/-）-THBG]是由DNA与（+/-）-BDO2反应形成的，另一种非对映异构体（内消旋 - THBG）是由DNA与内消旋 - BDO2反应形成的。在监测的BD暴露10天期间及暴露后6天，与大鼠相比，小鼠肝脏DNA中的（+/-）-THBG和内消旋 - THBG明显更多。在大鼠肝脏的所有时间点，（+/-）-THBG比内消旋 - THBG多2倍。在小鼠肝脏中暴露于BD 10天后，（+/-）-THBG（3.9个加合物/10⁶个正常碱基）也比内消旋 - THBG（2.2个加合物/10⁶个正常碱基）多出近2倍。然而，在暴露于BD 6天后，小鼠肝脏中的（+/-）-THBG（1.2个加合物/10⁶个正常碱基）和内消旋 - THBG（1.0个加合物/10⁶个正常碱基）含量几乎相等。此外，与大鼠肝脏DNA相比，暴露于BD 6天后小鼠肝脏DNA中的两种THBG非对映异构体多出近5倍。（+/-）-THBG和内消旋 - THBG在小鼠肝脏中的半衰期（分别为4.1天和5.5天）似乎比在大鼠肝脏中（分别为3.6天和4.0天）略长。这些加合物在小鼠体内的明显持久性可能导致该物种对BD诱导的致癌作用易感性增加。（+/-）-THBG和内消旋 - THBG也有可能源自DNA与BDO2的水解产物1,2 - 二羟基 - 3,4 - 环氧丁烷（DHEB）的反应。令人惊讶的是，在大多数研究BDO2的诱变和致癌潜力的研究中，仅使用了市售的（+/-）-BDO2。鉴于目前的研究结果，需要进行更多研究以确定内消旋 - BDO2和作为诱变剂和致癌物的内消旋 - THBG的前体DHEB的效力。
