Ríos-Blanco M N, Plna K, Faller T, Kessler W, Håkansson K, Kreuzer P E, Ranasinghe A, Filser J G, Segerbäck D, Swenberg J A
Curriculum in Toxicology, University of North Carolina at Chapel Hill 27599, USA.
Mutat Res. 1997 Oct 31;380(1-2):179-97. doi: 10.1016/s0027-5107(97)00135-8.
The results from mutagenic and carcinogenic studies of propylene oxide (PO) and the current efforts to develop molecular dosimetry methods for PO-DNA adducts are reviewed. PO has been shown to be active in several bacterial and mammalian mutagenicity tests and induces site of contact tumors in rodents after long-term administration. Quantitation of N7-(2-hydroxypropyl)guanine (7-HPG) in nasal and hepatic tissues of male F344 rats exposed to 500 ppm PO (6 h/day; 5 days/week for 4 weeks) by inhalation was performed to evaluate the potential of high concentrations of PO to produce adducts in the DNA of rodent tissues and to obtain information necessary for the design of molecular dosimetry studies. The persistence of 7-HPG in nasal and hepatic tissues was studied in rats killed three days after cessation of a 4-week exposure period. DNA samples from exposed and untreated animals were analyzed for 7-HPG by two different methods. The first method consisted of separation of the adduct from DNA by neutral thermal hydrolysis, followed by electrophoretic derivatization of the adduct and gas chromatography-high resolution mass spectrometry (GC-HRMS) analysis. The second method utilized 32P-postlabeling to quantitate the amount of this adduct in rat tissues. Adducts present in tissues from rats killed immediately after cessation of exposure were 835.4 +/- 80.1 (respiratory), 396.8 +/- 53.1 (olfactory) and 34.6 +/- 3.0 (liver) pmol adduct/mumol guanine using GC-HRMS. Lower values, 592.7 +/- 53.3, 296.5 +/- 32.6 and 23.2 +/- 0.6 pmol adduct/mumol guanine were found in respiratory, olfactory and hepatic tissues of rats killed after three days of recovery. Analysis of the tissues by 32P-postlabeling yielded the following values: 445.7 +/- 8.0 (respiratory), 301.6 +/- 49.2 (olfactory) and 20.6 +/- 1.8 (liver) pmol adduct/mumol guanine in DNA of rats killed immediately after exposure cessation and 327.1 +/- 21.7 (respiratory), 185.3 +/- 29.2 (olfactory) and 15.7 +/- 0.9 (liver) pmol adduct/mumol guanine after recovery. Current methods of quantitation did not provide evidence for the endogenous formation of this adduct in control animals. These studies demonstrated that the target tissue for carcinogenesis has much greater alkylation of DNA than liver, a tissue that did not exhibit a carcinogenic response.
本文综述了环氧丙烷（PO）的致突变性和致癌性研究结果，以及目前开发PO-DNA加合物分子剂量测定方法的相关工作。PO已在多种细菌和哺乳动物致突变性试验中表现出活性，长期给药后可在啮齿动物中诱发接触部位肿瘤。对吸入500 ppm PO（每天6小时；每周5天，共4周）的雄性F344大鼠的鼻腔和肝脏组织中的N7-(2-羟丙基)鸟嘌呤（7-HPG）进行定量分析，以评估高浓度PO在啮齿动物组织DNA中产生加合物的可能性，并获取分子剂量测定研究设计所需的信息。在为期4周的暴露期结束后3天处死的大鼠中，研究了7-HPG在鼻腔和肝脏组织中的持久性。通过两种不同方法对暴露组和未处理组动物的DNA样本进行7-HPG分析。第一种方法是通过中性热水解从DNA中分离加合物，然后对加合物进行电泳衍生化，并进行气相色谱-高分辨率质谱（GC-HRMS）分析。第二种方法利用32P后标记法定量大鼠组织中该加合物的含量。使用GC-HRMS分析，暴露结束后立即处死的大鼠组织中的加合物含量分别为：呼吸道835.4±80.1、嗅觉组织396.8±53.1和肝脏34.6±3.0 pmol加合物/μmol鸟嘌呤。恢复3天后处死的大鼠呼吸道、嗅觉和肝脏组织中的加合物含量较低，分别为592.7±53.3、296.5±32.6和23.2±0.6 pmol加合物/μmol鸟嘌呤。通过32P后标记法分析组织得到以下结果：暴露结束后立即处死的大鼠DNA中，呼吸道为445.7±8.0、嗅觉组织为301.6±49.2和肝脏为20.6±1.8 pmol加合物/μmol鸟嘌呤；恢复后分别为327.1±21.7、185.3±29.2和15.7±0.9 pmol加合物/μmol鸟嘌呤。目前的定量方法未提供对照动物中该加合物内源性形成的证据。这些研究表明，致癌作用的靶组织DNA的烷基化程度远高于肝脏，而肝脏并未表现出致癌反应。
