Department of Environmental Toxicology, Texas Tech University, Lubbock, Texas, USA.
Environ Toxicol Chem. 2013 Jun;32(6):1295-303. doi: 10.1002/etc.2188. Epub 2013 Apr 19.
Absorption, distribution, and biotransformation are 3 critical aspects affecting toxicant action in animals. In the present study, B6C3F1 mice (Mus musculus) were exposed for 28 d to contaminated feed that contained 1 of 5 different hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) concentrations: 0 mg/kg, 0.5 mg/kg, 5 mg/kg, 50 mg/kg, and 500 mg/kg. The authors quantified RDX and its reductive transformation products hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in the stomach, intestine, plasma, liver, and brain of these mice. Average RDX concentrations followed a dose-dependent pattern for all matrices tested. No controls had concentrations above limits of detection. Average RDX concentrations in tissues of exposed mice ranged from 11.1 ng/mL to 182 ng/mL, 25.6 ng/g to 3319 ng/g, 123 ng/g to 233 ng/g, 144 ng/g to 35 900 ng/g, and 51.1 ng/g to 2697 ng/g in the plasma, brain, liver, stomach, and intestine, respectively. A considerable amount of RDX was present in the brain, especially in the highest-exposure group. This is consistent with the widely observed central nervous system effects caused by γ-aminobutyric acid inhibition associated with RDX exposure. N-nitroso metabolites of RDX were also present in tested tissues in a dose-dependent pattern. Average MNX concentrations in the stomachs of mice exposed to RDX ranged from nondetectable in control exposures to 490 ng/g in the highest-exposure groups. In the brain, MNX accumulated at a maximum average concentration of 165.1 ng/g, suggesting the potential formation of MNX from RDX within the brain. At higher exposures, DNX and TNX were present in the stomach, plasma, and brain of mice. The presence of RDX metabolites at notable amounts in different tissues suggests that RDX can transform into its N-nitroso metabolites in vivo by an undefined mechanism.
吸收、分布和生物转化是影响动物中毒物作用的 3 个关键方面。在本研究中，B6C3F1 小鼠（Mus musculus）暴露于含有 5 种不同六氢-1,3,5-三硝基-1,3,5-三嗪（RDX）浓度的污染饲料中 28 天：0mg/kg、0.5mg/kg、5mg/kg、50mg/kg 和 500mg/kg。作者定量测定了 RDX 及其还原转化产物六氢-1-亚硝基-3,5-二硝基-1,3,5-三嗪（MNX）、六氢-1,3-二亚硝基-5-硝基-1,3,5-三嗪（DNX）和六氢-1,3,5-三亚硝基-1,3,5-三嗪（TNX）在这些小鼠的胃、肠、血浆、肝脏和大脑中的含量。所有测试基质的平均 RDX 浓度均呈现出剂量依赖性模式。没有对照样品的浓度超过检测限。暴露于 RDX 的小鼠组织中的平均 RDX 浓度范围为 11.1ng/mL 至 182ng/mL、25.6ng/g 至 3319ng/g、123ng/g 至 233ng/g、144ng/g 至 35900ng/g 和 51.1ng/g 至 2697ng/g 在血浆、大脑、肝脏、胃和肠中。相当数量的 RDX 存在于大脑中，尤其是在最高暴露组中。这与广泛观察到的 RDX 暴露引起的γ-氨基丁酸抑制相关的中枢神经系统效应一致。RDX 的 N-亚硝化物代谢物也以剂量依赖性模式存在于测试组织中。RDX 暴露组小鼠胃中的平均 MNX 浓度从对照样品中无法检测到到最高暴露组的 490ng/g。在大脑中，MNX 积累的平均浓度最高为 165.1ng/g，表明 MNX 可能是 RDX 在大脑内形成的。在更高的暴露水平下，DNX 和 TNX 存在于小鼠的胃、血浆和大脑中。不同组织中存在大量的 RDX 代谢物表明，RDX 可以通过未定义的机制在体内转化为其 N-亚硝化物代谢物。
