title: Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.
abstract: The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug-drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics.
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Wu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.|Institute of Chinese Meteria Medica, China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Lin
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Li
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Guiyu
authors.initials: G
authors.lastname: Zhang
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Shugui
authors.initials: S
authors.lastname: He
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Rilan
authors.initials: R
authors.lastname: Ou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.|State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.|State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Lu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000157:Aconitine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D004347:Drug Interactions; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000201:enzymology; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D015533:Transcriptional Activation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; C047307:benzoylaconine; C047306:aconine; D000157:Aconitine