猪胆粉中结合型胆甾酸的化学成分及生物活性研究
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摘要
猪胆粉为猪科动物猪Sus scrofa domestica Brisson胆汁的干燥品,味苦、性寒,归肝、胆、肺、大肠经,具有清热、润燥、解毒、止咳平喘的功效,为2010版《中华人民共和国药典》收载品种。猪胆粉中的主要化学成分为胆汁酸类,包括水溶性结合型胆酸和脂溶性游离型胆酸。现代药理学研究表明胆汁酸具有抗菌、抗炎、抗癌、利胆、降血脂等生物活性。受科学技术发展的限制,以前对猪胆粉的研究主要集中在其游离型胆酸,对结合型胆酸研究较少,而胆汁酸以结合型胆酸为主。本课题从提取分离、结构鉴定、定量分析、药理活性等方面对猪胆粉中的结合型胆酸进行系统研究,为猪胆粉的进一步开发利用,寻找创新药物奠定实验基础。
一、猪胆粉中结合型胆酸的分离及制备
本实验将猪胆粉药材用95%乙醇超声提取后,分别用硅胶干柱层析、硅胶柱层析、制备型高效液相色谱和高速逆流色谱等分离方法对猪胆粉中的成分进行分离,得到8个化合物,其中6个为结合型胆酸。通过理化常数测定及光谱法分析(UV, IR, MS,1HNMR和13C NMR)鉴定了结构,分别为：胆固醇、猪去氧胆酸、甘氨猪胆酸、甘氨猪去氧胆酸、甘氨鹅去氧胆酸、牛磺猪胆酸、牛磺猪去氧胆酸和牛磺鹅去氧胆酸。此外,本实验采用化学混酐法合成了牛磺猪去氧胆酸单体化合物。这些研究为进一步的药物分析及药理学研究提供了物质基础。
二、猪胆粉中结合型胆酸的定量分析
本课题承担了2010版《中华人民共和国药典》标准研究课题：猪胆粉含量测定项的修订。实验中采用HPLC法,考察了不同产地猪胆粉药材中牛磺猪去氧胆酸的含量,制定了其含量限度。以上研究结果经黑龙江省食品药品检验所复核后,通过国家药典委员会审核收入2010版《中华人民共和国药典》(增补本)中。此外,实验中分别采用HPLC和MEKC法对猪胆粉中的多种结合型胆酸进行同时测定,并建立了猪胆粉的特征图谱,为猪胆粉药材的质量控制提供科学依据。
三、猪胆粉药材中结合型胆酸的生物活性研究
采用二甲苯致小鼠耳肿胀法和角叉菜胶致大鼠足趾肿胀法评价了结合型总胆酸的抗炎作用；以小鼠热板法、醋酸扭体法和光照甩尾法评价了结合型总胆酸的镇痛作用。实验结果显示结合型总胆酸能抑制二甲苯致小鼠耳肿胀及角叉菜胶致大鼠足趾肿胀,增加小鼠热板法痛阈时间,延长小鼠光照甩尾潜伏期,抑制醋酸扭体法扭体次数,表明结合型总胆酸具有良好的抗炎镇痛作用。
采用三硝基苯磺酸诱导的溃疡性结肠炎模型小鼠首次研究了结合型总胆酸和牛磺猪去氧胆酸对实验性溃疡性结肠炎的治疗作用。研究发现,结合型总胆酸和牛磺猪去氧胆酸大、中、小剂量均能显著降低溃疡性结肠炎模型小鼠结肠组织中髓过氧化物酶活性和环氧合酶2的表达,并能显著降低小鼠血清中白介素6和肿瘤坏死因子α的水平,表明结合型总胆酸及牛磺猪去氧胆酸具有抗炎及促进组织修复作用,并能调节免疫,对实验性溃疡性结肠炎具有一定的治疗作用,为进一步的研究开发和临床应用提供科学依据。
Pulvis Fellis Suis (Chinese name Zhu Danfen) is the dried bile of Sus scrofa domestica Brisson. According to the Chinese Pharmacopoeia2010, it has been used extensively for removing toxic-heat, moistening dry, relieving cough and asthma. Bile acids, including free bile acids and conjugated bile acids, are the major components in Pulvis Fellis Suis. Modern pharmacological research indicates that these compounds display diverse biological activities, such as antibacterial, anti-inflammatory, and inhibitory proliferation of human promyelocytic leukemia cell line HL-60as well as accelerating bile secretion, treating gallstones, and lowering blood lipids. With the restriction of development of science and technology, studies on bile acids are mainly in free bile acids, but conjugated bile acids are the main components. In our research, we made a systematic study on conjugated bile acids in Pulvis Fellis Suis, including extraction and separation, structure identification, quantitative analysis and pharmacology activities. The detailed descriptions are listed below.
Part one:Separation and preparation of conjugated cholic acids
Pulvis Fellis Suis was extracted with95%ethanol. After removing the solvent, the ethanol extracts were subjected to silica gel column chromatography, preparative high performance liquid chromatography and high speed countercurrent chromatography to obtain eight compounds, including six conjugated cholic acids. Their structures were elucidated by physical and chemical data and spectroscopic analyses (UV, IR,MS、1H NMR and13C NMR), they are cholesterol, glycohyocholic acid, glycohyodeoxycholic acid, glycochenodeoxycholic acid, taurohyocholic acid, taurohyodeoxycholic acid and taurochenodeoxycholic acid. In addition, taurohyodeoxycholic acid was synthesized by chemical method. The research provided material basis for quantitative analysis and pharmacology study.
Part two:Quantitative analysis of conjugated cholic acids
We assumed the Project of Standard Research of Chinese Pharmacopoeia2010:Revision quantitative analysis method for Pulvis Fellis Suis. A HPLC method has been developed for the determination of taurohyodeoxycholic acid in Pulvis Fellis Suis, and the limitation was established. After the results were checked by Hei longjiang Food and Drug Administration and National Pharmacopoeia Committee, the quantitative method was listed in Chinese Pharmacopoeia2010(Supplement). In addition, HPLC and MEKC methods have been developed for the simultaneous determination of conjugated cholic acids and establishment of characteristic figure, provide the scientific basis for Pulvis Fellis Suis.
Part three: Pharmacology activity research of Pulvis Fellis Suis
The anti-inflammatory and analgesic effects of total conjugated cholic acid was evaluated by xylene-induced mice ear edema test, carrageenan-induced rat paw edema test, mice heat radiation tail flick assay, mice acetic acid writhing test and hot-plate test. The results indicated that total conjugated cholic acid could inhibit mice ear swelling degree, rats foot swelling degree and tail flick latency, increase mice pain threshold value, decrease mice twist time, it have the anti-inflammatory and analgesic effects.
The anti-inflammatory effects of total conjugated cholic acid and taurohyodeoxycholic acid (THDCA) on acute ulcerative colitis were evaluated by trinitrobenzene sulfonic acid induced ulcerative colitis model in mice. The results demonstrated that total conjugated cholic acid and THDCA could significantly decreased colonic MPO activity, TNF-a, IL-6serum levels and the expression of COX-2in colon compared with TNBS induced ulcerative colitis model group. Moreover, total conjugated cholic acid and THDCA attenuated the macroscopic colonic damage and the histopathological changes induced by TNBS. All the effects of these parameters suggested that total conjugated cholic acid and THDCA from Pulvis Fellis Suis have protective effects in TNBS-induced ulcerative colitis which might be due to their anti-inflammatory activities, and that they may have therapeutic value in the setting of inflammatory bowel disease.
一、猪胆粉中结合型胆酸的分离及制备
本实验将猪胆粉药材用95%乙醇超声提取后,分别用硅胶干柱层析、硅胶柱层析、制备型高效液相色谱和高速逆流色谱等分离方法对猪胆粉中的成分进行分离,得到8个化合物,其中6个为结合型胆酸。通过理化常数测定及光谱法分析(UV, IR, MS,1HNMR和13C NMR)鉴定了结构,分别为：胆固醇、猪去氧胆酸、甘氨猪胆酸、甘氨猪去氧胆酸、甘氨鹅去氧胆酸、牛磺猪胆酸、牛磺猪去氧胆酸和牛磺鹅去氧胆酸。此外,本实验采用化学混酐法合成了牛磺猪去氧胆酸单体化合物。这些研究为进一步的药物分析及药理学研究提供了物质基础。
二、猪胆粉中结合型胆酸的定量分析
本课题承担了2010版《中华人民共和国药典》标准研究课题：猪胆粉含量测定项的修订。实验中采用HPLC法,考察了不同产地猪胆粉药材中牛磺猪去氧胆酸的含量,制定了其含量限度。以上研究结果经黑龙江省食品药品检验所复核后,通过国家药典委员会审核收入2010版《中华人民共和国药典》(增补本)中。此外,实验中分别采用HPLC和MEKC法对猪胆粉中的多种结合型胆酸进行同时测定,并建立了猪胆粉的特征图谱,为猪胆粉药材的质量控制提供科学依据。
三、猪胆粉药材中结合型胆酸的生物活性研究
采用二甲苯致小鼠耳肿胀法和角叉菜胶致大鼠足趾肿胀法评价了结合型总胆酸的抗炎作用；以小鼠热板法、醋酸扭体法和光照甩尾法评价了结合型总胆酸的镇痛作用。实验结果显示结合型总胆酸能抑制二甲苯致小鼠耳肿胀及角叉菜胶致大鼠足趾肿胀,增加小鼠热板法痛阈时间,延长小鼠光照甩尾潜伏期,抑制醋酸扭体法扭体次数,表明结合型总胆酸具有良好的抗炎镇痛作用。
采用三硝基苯磺酸诱导的溃疡性结肠炎模型小鼠首次研究了结合型总胆酸和牛磺猪去氧胆酸对实验性溃疡性结肠炎的治疗作用。研究发现,结合型总胆酸和牛磺猪去氧胆酸大、中、小剂量均能显著降低溃疡性结肠炎模型小鼠结肠组织中髓过氧化物酶活性和环氧合酶2的表达,并能显著降低小鼠血清中白介素6和肿瘤坏死因子α的水平,表明结合型总胆酸及牛磺猪去氧胆酸具有抗炎及促进组织修复作用,并能调节免疫,对实验性溃疡性结肠炎具有一定的治疗作用,为进一步的研究开发和临床应用提供科学依据。
Pulvis Fellis Suis (Chinese name Zhu Danfen) is the dried bile of Sus scrofa domestica Brisson. According to the Chinese Pharmacopoeia2010, it has been used extensively for removing toxic-heat, moistening dry, relieving cough and asthma. Bile acids, including free bile acids and conjugated bile acids, are the major components in Pulvis Fellis Suis. Modern pharmacological research indicates that these compounds display diverse biological activities, such as antibacterial, anti-inflammatory, and inhibitory proliferation of human promyelocytic leukemia cell line HL-60as well as accelerating bile secretion, treating gallstones, and lowering blood lipids. With the restriction of development of science and technology, studies on bile acids are mainly in free bile acids, but conjugated bile acids are the main components. In our research, we made a systematic study on conjugated bile acids in Pulvis Fellis Suis, including extraction and separation, structure identification, quantitative analysis and pharmacology activities. The detailed descriptions are listed below.
Part one:Separation and preparation of conjugated cholic acids
Pulvis Fellis Suis was extracted with95%ethanol. After removing the solvent, the ethanol extracts were subjected to silica gel column chromatography, preparative high performance liquid chromatography and high speed countercurrent chromatography to obtain eight compounds, including six conjugated cholic acids. Their structures were elucidated by physical and chemical data and spectroscopic analyses (UV, IR,MS、1H NMR and13C NMR), they are cholesterol, glycohyocholic acid, glycohyodeoxycholic acid, glycochenodeoxycholic acid, taurohyocholic acid, taurohyodeoxycholic acid and taurochenodeoxycholic acid. In addition, taurohyodeoxycholic acid was synthesized by chemical method. The research provided material basis for quantitative analysis and pharmacology study.
Part two:Quantitative analysis of conjugated cholic acids
We assumed the Project of Standard Research of Chinese Pharmacopoeia2010:Revision quantitative analysis method for Pulvis Fellis Suis. A HPLC method has been developed for the determination of taurohyodeoxycholic acid in Pulvis Fellis Suis, and the limitation was established. After the results were checked by Hei longjiang Food and Drug Administration and National Pharmacopoeia Committee, the quantitative method was listed in Chinese Pharmacopoeia2010(Supplement). In addition, HPLC and MEKC methods have been developed for the simultaneous determination of conjugated cholic acids and establishment of characteristic figure, provide the scientific basis for Pulvis Fellis Suis.
Part three: Pharmacology activity research of Pulvis Fellis Suis
The anti-inflammatory and analgesic effects of total conjugated cholic acid was evaluated by xylene-induced mice ear edema test, carrageenan-induced rat paw edema test, mice heat radiation tail flick assay, mice acetic acid writhing test and hot-plate test. The results indicated that total conjugated cholic acid could inhibit mice ear swelling degree, rats foot swelling degree and tail flick latency, increase mice pain threshold value, decrease mice twist time, it have the anti-inflammatory and analgesic effects.
The anti-inflammatory effects of total conjugated cholic acid and taurohyodeoxycholic acid (THDCA) on acute ulcerative colitis were evaluated by trinitrobenzene sulfonic acid induced ulcerative colitis model in mice. The results demonstrated that total conjugated cholic acid and THDCA could significantly decreased colonic MPO activity, TNF-a, IL-6serum levels and the expression of COX-2in colon compared with TNBS induced ulcerative colitis model group. Moreover, total conjugated cholic acid and THDCA attenuated the macroscopic colonic damage and the histopathological changes induced by TNBS. All the effects of these parameters suggested that total conjugated cholic acid and THDCA from Pulvis Fellis Suis have protective effects in TNBS-induced ulcerative colitis which might be due to their anti-inflammatory activities, and that they may have therapeutic value in the setting of inflammatory bowel disease.
引文
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