School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
J Ethnopharmacol. 2019 Jan 10;228:164-178. doi: 10.1016/j.jep.2018.09.022. Epub 2018 Sep 15.
In traditional Chinese medicine, processed aconite root (lateral root of Aconitum carmichaelii Debx.) is used as the principle herb of the Si-Ni decoction (SND) formula due to its cardiotonic effect, while its cardiotoxicity and neurotoxicity caused by diester and monoester diterpenoid alkaloids are reduced by compatibility of dried ginger and honey-processed liquorice in SND.
To investigate the detoxification of processed aconite root by compatibility of SND from the perspective of intestinal absorption with metabolism in intestinal bacteria.
Decoctions of processed aconite root (AD), processed aconite root and honey-processed liquorice (ALD), and SND with the same amount of each herb were prepared, then were incubated in human intestinal bacteria juice (IBJ) in vitro for different durations. Bidirectional transmembrane transports of these decoctions and their IBJ-incubated decoctions were conducted on Caco-2 monolayers. Correlation between efflux ratios changes of benzoylmesaconine, benzoylaconine, benzoylhypaconine (monoester-diterpenoid alkaloids, MDAs) and hypaconitine (diester-diterpenoid alkaloids) from processed aconite root, and metabolic trends of compounds from honey-processed liquorice and dried ginger were also performed.
The absorption of MDAs from processed aconite root was increased by combination with honey-processed liquorice in ALD, but they were decreased significantly by the addition of dried ginger in SND. Take benzoylhypaconine for example, the P soared from (3.13 ± 0.18) × 10 cm/s in AD to (23.32 ± 3.51) × 10 cm/s in ALD, while it dropped to (1.12 ± 0.17) × 10 cm/s in SND. When herb combined decoctions metabolised by intestinal bacteria for 12 h, the efflux ratio of benzoylhypaconine were both increased from 0.56 to 1.21 in ALD and from 1.10 to 2.61 in SND, which was correlative with the generation of davidigenin and glycyrrhetic acid (the metabolites of chalcones and pentacyclic triterpenoids from liquorice) in ALD and with the metabolism of [6]-gingerol (the major compound from dried ginger) in SND, respectively.
Compatibility of SND altered the intestinal absorption of toxic MDAs and hypaconitine from processed aconite root. In SND, dried ginger rather than honey-processed liquorice played the role of detoxification of these toxic compounds in the intestinal absorption. The intestinal detoxification of SND was significantly and strongly correlative with metabolism of dried ginger and honey-processed liquorice by intestinal bacteria, simultaneously.
在传统的中医中，炮制乌头（川乌的侧根）被用作四逆汤（SND）配方的主要草药，因为它具有强心作用，而其通过干姜和蜜炙甘草在 SND 中的配伍而降低的二酯和单酯二萜生物碱的心脏毒性和神经毒性。
从肠道吸收和肠道细菌代谢的角度研究 SND 对炮制乌头根的解毒作用。
制备炮制乌头根（AD）、炮制乌头根和蜜炙甘草（ALD）以及含有相同草药量的 SND 汤，然后在体外用人肠菌汁（IBJ）中孵育不同时间。在 Caco-2 单层上进行这些汤剂及其 IBJ 孵育汤剂的双向跨膜转运。还对来自炮制乌头根的苯甲酰次乌头碱、苯甲酰乌头碱、苯甲酰新乌头碱（单酯二萜生物碱，MDAs）和新乌头碱（二酯二萜生物碱）的流出比变化与蜜炙甘草和干姜化合物的代谢趋势之间进行了相关性分析。
与蜜炙甘草结合的 ALD 中，炮制乌头根的 MDAs 吸收增加，但在 SND 中加入干姜后，MDAs 的吸收显著减少。以苯甲酰新乌头碱为例，其从 AD 中的 P 从（3.13±0.18）×10cm/s 飙升至 ALD 中的（23.32±3.51）×10cm/s，而在 SND 中则降至（1.12±0.17）×10cm/s。当肠菌代谢的草药汤剂孵育 12 小时时，苯甲酰新乌头碱的流出比在 ALD 中从 0.56 增加到 1.21，在 SND 中从 1.10 增加到 2.61，这与 ALD 中chalcones 和五环三萜类化合物的代谢物大卫醇和 SND 中[6]-姜酚（干姜的主要化合物）的代谢分别相关。
SND 的配伍改变了炮制乌头根中有毒的 MDAs 和新乌头碱的肠道吸收。在 SND 中，干姜而不是蜜炙甘草在肠道吸收中起到了这些有毒化合物解毒的作用。SND 的肠道解毒作用与肠道细菌对干姜和蜜炙甘草的代谢密切相关。
