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藏药佐太中硫化汞大鼠胃肠转化形态与吸收研究
李 岑
学位类型博士
导师魏立新 ; 杜玉枝
2014-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业生物学(藏药毒理)
关键词藏药 佐太 硫化汞 胃肠化学转化 肠道吸收
摘要药物的作用不仅与剂量,还与其在体内的转化形态紧密相关。目前,重金属安全性问题已对藏药的生存形成了极大挑战。佐太,则是含汞藏药的典型代表,安全性备受现代社会质疑,但其长期的临床应用并未发现有明显毒性,这个矛盾是所有含重金属传统药物都迫切需要解决的难题。而口服药物在胃肠与血中的转化形态,是其在体内发挥效应的最为直接的物质基础,因此揭示佐太在胃肠中汞的转化形态与吸收,是客观评价藏药重金属安全性的一个关键突破口。为此,本文在离体和在体实验的基础上,重点利用同步辐射微区X-射线荧光(μ-XRF)、X-射线吸收精细结构(XAFS)等技术,对佐太中汞的理化表征、在胃肠微区分布与转化吸收、在血中化学形态、在肾中微区分布与存在形态等,进行探索,主要研究结果如下:
精确理化表征:1)发现佐太中Hg为正二价,配位数为4,配位原子为S;2)佐太中主要存在β-HgS、S8及少量(或无)α-HgS,此外有少量C、Fe1.05S0.95、Cu6S6、Cu1.8S等;3)佐太是一种具微纳米尺度的传统药物,粒径多在100~800 nm。
在胃中微区分布与转化形态:1)发现佐太中汞在大鼠离体胃中仅分布在粘膜层表面,而在粘膜层、粘膜下层、肌层和浆膜层均无分布;2)佐太中汞在胃内容物中为正二价,以β-HgS以及少量的HgCys2等形式存在,表明佐太中难溶性的硫化汞在胃中可以进行形态转化,但很难在此处吸收。
在十二指肠中微区分布与转化吸收:1)发现在大鼠离体十二指肠中,佐太中汞主要分布在肠腔和粘膜层表面,还有少量分布在粘膜层和粘膜下层,表明佐太中汞能够在肠中吸收;2)佐太中汞在十二指肠内容物为正二价,主要为β-HgS及少量 HgCys2等,表明佐太中不溶性的硫化汞可在肠中转化为半胱氨酸汞;3)利用离体外翻肠囊研究发现,十二指肠可直接吸收HgCys2和游离态Hg2+,对Hg2+的吸收高于HgCys2,推测氨基酸/多肽载体、有机阴离子载体、二价金属离子载体可能参与这些化学形态的跨膜吸收。
在血液中化学形态:大鼠给药佐太3个月后,发现血液中汞的化学形态主要为HgCys2及少量游离态Hg2+等,另外还可能存在大量的巯基多肽结合汞与巯基蛋白结合汞等形式,初步揭示了藏药佐太在机体内直接发挥生物学效应的可能物质。
在肾脏中微区分布与存在形态:1)发现佐太中汞在小鼠(给药3.5个月)肾脏皮质层分布量较高,尤其是内侧缘皮质,而在髓质区分布相对较少;2)发现佐太中汞在肾脏中除HgCys2外,可能还存在汞的巯基蛋白复合物。
本论文揭示了佐太中汞进入机体前、胃肠中、机体内的化学存在形态与微区分布规律,对于客观评价重金属藏药——佐太安全性和探索肠上皮细胞参与汞跨膜吸收的载体/途径具有重要意义。
其他摘要  The Effects of drugs is not only related to its dose, but also is closely related to its converted chemical forms in vivo. At present, the heavy metal safety problem has exerted a great challenge on the survival of Tibetan medicine. Zuotai (gTso Thal) is a representative of Tibetan drugs containing heavy metals, and its safety is being questioned seriously. On the contrary, it appears no obvious toxicity in the long-term clinical application. This contradiction is a difficult problem that all traditional medicines containing heavy metals need to address. The converted chemical species of drugs in gastrointestine and blood are the directly substantial foundation playing biological effects in the body. Therefore, the disclosure of the converted chemical forms and absorption of Zuotai in gastrointestine is a key breakthrough for evaluating the safety of Tibetan medicine containing heavy metals.
  Therefore, Micro X-ray Fluorescence (μ-XRF), X-ray Absorption Fine Structure (XAFS) and other technologies were used to explore the precise physico-chemical characterization, the micro-distribution and chemical species in gastrointestine and kidney, and the chemical form in blood. Besides, the converted chemical species of the mercury of Zuotai, which are absorbed in duodenum, is also explored. The main results are as follows:
  Physicochemical Characteristics: i. Zuotai mainly contain mercury(Hg) and sulfur(S), and other minor elements, such as iron(Fe), copper(Cu), silver(Ag), aluminum(Al), lead(Pb), arsenic(As), et al. ii. The ligand atoms of mercury in Zuotai are sulfur with positive divalent state and four coordination number. iii. β-HgS and S8 are main phase compositions in Zuotai. Besides, it also exists a small amount of C, Fe1.05S0.95, Cu6S6, Cu1.8S and so on. iv. Zuotai is a kind of ancient micro-nano drug, and its particle size is mainly in 100-800 nm, even less than 100 nm.
  Micro-distribution and Converted Species in Stomach: i. The mercury distributes on the surface of rat stomach mucous layer, and no mercury distribution in mucous layer, submucosa layer, muscular layer and serosa layer after treated by Zuotai. ii. The chemical valence of mercury from Zuotai in rat gastric contents is positive divalent state, and exists in the form of β-HgS and small amount of HgCys2. This indicated that mercury element from Zuotai can be converted other chemical species, but it is difficult absorbed in the stomach.
  Micro-distribution, Converted Species and Absorption in Stomach: i. Mercury mainly distributes in the tract and surface of rat duodenum after treated by Zuotai. Besides, it have also a small amount of mercury distribution in mucosal layer and submucosal layers. This suggests the mercury of Zuotai can be absorbed in the duodenum. ii. The mercury in intestinal contents is divalence, and exists in the forms of β-HgS, HgCys2 and others. This experiment suggests that insoluble mercuric sulfide of Zuotai can be converted to low toxic HgCys2 in the rat intestine. iii Using everted duodenal sac model, we found that rat duodenum can directly absorb HgCys2 and free divalent mercury ion (Hg2+), and found the absorption rate of duodenal Hg2+ was significantly higher than that of HgCys2. So, this propose a hypothesis that amino acid transporters, peptide transporters and organic anion carriers may be involved in the transportation of HgCys2 which a converted species from mercury of Zuotai, and the transportation of other a converted species, free Hg2, from mercuric sulfur in Zuotai, may be involved of divalent metal ion carrier.
  Chemical Forms of Mercury in Blood: The chemical species of mercury in rat blood mainly are HgCys2 and the conjugates of protein/polypeptide-Hg after 3 months administration with Zuotai. Besides, it also contains minor amount of free mercuric ion (Hg2+). This has revealed that the probable substance of directly exerting effects of Zuotai on body.
  Micro-distribution and Chemical Forms of Mercury in Kidney:i. There are high amount of mercury distribution in mice kidney cortex, especially in the medial edge of renal cortex, but just with low amount of distribution in medulla after 3.5 months administration with Zuotai. ii. It is found that the chemical species in mice kidney are HgCys2 and the conjugates of mercury and protein containing thiol.
  In summary, the present research has revealed the precise physico-chemical characteristics of Zuotai,the species of mercury from Zuotai in the gastrointestine, blood and kidney, the micro-distribution and absorption of mercury from Zuotai in gastrointestine and kidney. It has important implications for the safety evaluation of Tibetan medicine Zuotai and the exploration of mercury transmembrane transportation carriers/pathways in intestinal epithelial cells.
语种中文
文献类型学位论文
条目标识符http://210.75.249.4/handle/363003/4004
专题中国科学院西北高原生物研究所
推荐引用方式
GB/T 7714
李 岑. 藏药佐太中硫化汞大鼠胃肠转化形态与吸收研究[D]. 北京. 中国科学院研究生院,2014.
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