Guo Lei, Mei Nan, Dial Stacey, Fuscoe James, Chen Tao
Division of Systems Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA.
BMC Bioinformatics. 2007 Nov 1;8 Suppl 7(Suppl 7):S22. doi: 10.1186/1471-2105-8-S7-S22.
Comfrey (Symphytum officinale) is a perennial plant and has been consumed by humans as a vegetable, a tea and an herbal medicine for more than 2000 years. It, however, is hepatotoxic and carcinogenic in experimental animals and hepatotoxic in humans. Pyrrolizidine alkaloids (PAs) exist in many plants and many of them cause liver toxicity and/or cancer in humans and experimental animals. In our previous study, we found that the mutagenicity of comfrey was associated with the PAs contained in the plant. Therefore, we suggest that carcinogenicity of comfrey result from those PAs. To confirm our hypothesis, we compared the expression of genes and processes of biological functions that were altered by comfrey (mixture of the plant with PAs) and riddelliine (a prototype of carcinogenic PA) in rat liver for carcinogenesis in this study.
Groups of 6 Big Blue Fisher 344 rats were treated with riddelliine at 1 mg/kg body weight by gavage five times a week for 12 weeks or fed a diet containing 8% comfrey root for 12 weeks. Animals were sacrificed one day after the last treatment and the livers were isolated for gene expression analysis. The gene expressions were investigated using Applied Biosystems Rat Whole Genome Survey Microarrays and the biological functions were analyzed with Ingenuity Analysis Pathway software. Although there were large differences between the significant genes and between the biological processes that were altered by comfrey and riddelliine, there were a number of common genes and function processes that were related to carcinogenesis. There was a strong correlation between the two treatments for fold-change alterations in expression of drug metabolizing and cancer-related genes.
Our results suggest that the carcinogenesis-related gene expression patterns resulting from the treatments of comfrey and riddelliine are very similar, and PAs contained in comfrey are the main active components responsible for carcinogenicity of the plant.
聚合草（药用聚合草）是一种多年生植物，2000多年来一直被人类当作蔬菜、茶和草药食用。然而，它在实验动物中具有肝毒性和致癌性，在人类中具有肝毒性。吡咯里西啶生物碱（PAs）存在于许多植物中，其中许多会导致人类和实验动物的肝脏毒性和/或癌症。在我们之前的研究中，我们发现聚合草的致突变性与该植物中所含的PAs有关。因此，我们认为聚合草的致癌性源于这些PAs。为了证实我们的假设，在本研究中，我们比较了聚合草（含有PAs的植物混合物）和阔叶千里光碱（致癌PA的原型）处理大鼠肝脏后与致癌作用相关的基因表达和生物学功能过程的变化。
将6组大蓝Fisher 344大鼠，一组每周通过灌胃给予1 mg/kg体重的阔叶千里光碱，共5次，持续12周；另一组喂食含8%聚合草根的饲料，持续12周。在最后一次处理后一天处死动物，分离肝脏进行基因表达分析。使用应用生物系统大鼠全基因组检测微阵列研究基因表达，并使用英睿达通路分析软件分析生物学功能。虽然聚合草和阔叶千里光碱处理后显著改变的基因和生物学过程之间存在很大差异，但仍有许多与致癌作用相关的共同基因和功能过程。两种处理在药物代谢和癌症相关基因表达的倍数变化改变方面存在很强的相关性。
我们的结果表明，聚合草和阔叶千里光碱处理导致的致癌相关基因表达模式非常相似，聚合草中所含的PAs是该植物致癌性的主要活性成分。
