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目的:以“异类相制”理论为指导,观察雷公藤不同中药复方配伍后对雷公藤肝脏毒性的影响,并探讨其机制。方法:将SD大鼠随机分为8组,分别为:空白组、雷公藤单药组、清络通痹复方组、雷公藤多苷片组、雷公藤+生地黄组、雷公藤+三七组、雷公藤+青风藤组、雷公藤+僵蚕组,灌胃给药30d。以生化和病理检查综合评估肝毒性,并采用“Cocktail”底物探针法评价雷公藤的不同配伍对大鼠肝微粒体体外温孵体系中细胞色素P450酶(CYP450)各亚型的影响。结果:雷公藤单药组、雷公藤多苷片组、雷公藤+青风藤组、雷公藤+僵蚕组与空白组比较可见多项生化指标明显差异,服用清络通痹复方、配伍三七或生地黄可较单药组降低ALT、AST指标(P<0.01,P<0.05)。病理检查回示,雷公藤和不同配方组合应用后,肝细胞损伤程度减轻。各用药组较空白组CYP3A、CYP2C9、CYP2C19的特异性底物终浓度增高,其羟基化代谢产物终浓度下降(P<0.05,P<0.01),提示服用雷公藤可导致肝内CPY3A、CYP2C9,CPY2C19酶活性的下降。和单药组对比,雷公藤经配伍后均可改善单药对CYP3A和CYP2C19的抑制。其中,三七对改善雷公藤单药对CYP3A的抑制作用比较明显(P<0.05),而生地黄对改善雷公藤单药对CYP2C19的抑制作用比较明显(P<0.05)。结论:清络通痹复方配伍可明显减轻雷公藤的肝毒性。经一一拆方与雷公藤配伍后,发现雷公藤与生地黄和三七配伍后可减轻其肝毒性,其减毒机制可能与生地黄和三七缓解了雷公藤对CYP3A和CYP2C19的抑制相关。
OBJECTIVE: To investigate the effects of different traditional Chinese medicines (TCM) on the hepatic toxicity of Tripterygium wilfordii under the guidance of “heterogeneous phase ” theory and to explore its mechanism. Methods: Sprague-Dawley rats were randomly divided into 8 groups: blank group, tripterygium wilfordiii group, Qingluotongbi group, Tripterygium wilfordii tablet group, Tripterygium + Radix Rehmanniae group, Tripterygium wilfordii + Panax notoginseng Group, Tripterygium + Qingfengtu group, Tripterygium + silkworm group, gavage administration 30d. Hepatotoxicity was evaluated by biochemical and pathological examination. The “Cocktail” substrate probe method was used to evaluate the effect of different compatibility of Tripterygium on liver cytochrome P450 enzyme (CYP450) subtype in rat liver microsomal incubation system influences. Results: A number of biochemical indexes were significantly different between Tripterygium Wilfordii single group, Tripterygium wilfordii tablet group, Tripterygium wilfordii + Qingfengtu group, Tripterygium wilfordii + silkworm group and blank group. Taking Qingluotongbi Compound and compatibility three Seven or Rehmannia can reduce ALT, AST index than single drug group (P <0.01, P <0.05). Pathological examination showed that Tripterygium and a combination of different formulations, the degree of lessened liver cell damage. The final concentrations of specific substrates of CYP3A, CYP2C9 and CYP2C19 in each treatment group were increased, and the final concentrations of hydroxylated metabolites were decreased (P <0.05, P <0.01), suggesting that administration of Tripterygium wilfordii could result in intrahepatic CPY3A, CYP2C9, CPY2C19 enzyme activity decreased. Compared with the single drug group, Tripterygium could improve the inhibition of CYP3A and CYP2C19 by single drug after compatibility. Among them, the effect of Sanqi on the inhibition of Tripterygium wilfordii against CYP3A was more obvious (P <0.05), while the effect of Radix Rehmanniae on the inhibition of Tripterygium wilfordii against CYP2C19 was more obvious (P <0.05). Conclusion: Qingluotongbi compound prescription can obviously reduce the toxicity of Tripterygium wilfordii. Tripterygium wilfordii compatibility after one by one and found that Tripterygium and Rehmanniae and Panax notoginseng can reduce its liver toxicity, and its attenuated mechanism may be relieved Tripterygium Tripterygium on CYP3A and CYP2C19 inhibition .