白附子对正常和肾阳虚证大鼠毒性作用的差异

Difference of Toxic Effect of Rhizoma Typhonii on Normal and Kidney-yang Insufficiency Rats

目的从代谢组学角度探讨正常和肾阳虚证大鼠对白附子的毒性反应的差异。方法将80只SD雄性大鼠随机分为肾阳虚证模型组和正常组,采用肌肉注射氢化可的松琥珀酸钠的方法造模,造模结束后,把两组大鼠随机分为低剂量、小剂量、中剂量和大剂量给药组和空白组,每组8只;对各给药组大鼠连续14d灌胃给予不同浓度的白附子溶液,剂量依次为0.32、0.64、1.28、2.56g/(kg·d),空白组给予生理盐水;末次给药24h后取血浆,采用高效液相色谱-质谱联用的代谢组学技术检测血清促肾上腺皮质激素(ACTH)、皮质醇(COR)、环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)。结果氢化可的松造模可引起血浆代谢物溶血磷脂酰乙醇胺(LPE)水平和溶血磷脂酰胆碱(LPC)水平的下调。正常大鼠和肾阳虚证大鼠给予白附子后两者内源性代谢产物存在差异,随着白附子剂量的增加,正常大鼠LPC水平和LPE水平有下降的趋势,而模型大鼠LPC和LPE水平基本保持在稳定状态。结论肾阳虚证大鼠对白附子的毒性反应低于正常大鼠,印证了在证候理论指导下进行中药毒性评价的合理性。

Objective To explore the difference of toxic effect of Baifuzi （Rhizome Typhonii） on normal and kidney-yang in- sufficiency rats from the viewpoint of metabonomics. Methods Eighty SD male rats were randomized into normal group and kidney yang deficiency model group. After making the kidney yang deficiencyt model by injecting intramuscularly hydrocortiso- ni natrii succinas, the rats of two groups were randomized into the low, small, medium, large dose sub-groups and blank group with 8 in each. The medicated rats were administered by lavage the different concentrations of Rhizome Typhonii every day for 14 days, and the dosage was 0.32, 0.64, 1.28, 2.56g/（kg · d）. The blank group was given normal saline. Twenty-four hours after the last medication, the blood plasma ＇was obtained and used for testing adrenocorticotropic hormone （ACTH）, cortisol （COR）, cyclic adenosin monophosphate （cAMP） and cyclic guanosine monophosphate （cGMP） with the liquid chromatogra- phy-mass spectrometry （LC/MS） metabolomics technique. Results Hydrocortisone brought about the decline of lysophosphatidyl ethanolamine （LPE） and lysophosphatidyl choline （LPC） in blood plasma metabolite. There was a difference of endogenetic metabolite between the normal and model rats caused by white prepared lateral root of aconite. With the dose increase, a trend of decline of LPC and LPE of normal rats existed, however, those of the model rats kept basically stable. Conclusion The toxic reaction of the kidney-yang insufficiency rats to Rhizome Typhonii was weaker than that of the normal rats, confirmed the rationality of evaluating the toxicity of Chinese medicines based on TCM syndrome theory.