Isoquinoline alkaloids such as coptisine, berberine and palmatine isolated from the rhizome of Coptis japonica

palmatine isolated from the rhizome of Coptis japonica MAKINO have been demonstrated to exert wide ranges of biological and pharmacological activities. In particular, the major medically important isoquinoline alkaloid, berberine, has been extensively studied and recently reported to display beneficial effects in the treatment of diabetes, obesity and hyperlipidemia, while both coptisine and palmatine have been reported to exhibit a limited number of biological activities compared with berberine. These three isoquinoline alkaloids possess the same tetracyclic structure but differ in the nature of the substituents on the benzo ring, comprising methylene dioxy and/or dimethoxy substituents (Fig. 1). Regardless of the similarities in their structures, numerous studies have indicated that these three isoquinoline alkaloids appear to possess distinct activities with different potencies. For example, the potencies of the antibacterial activities against intestinal bacteria are in the order of berberine, palmatine and coptisine. The inhibitory effect on dopamine biosynthesis in PC12 cells is observed with berberine and palmatine, but not with coptisine. The inhibitory activity of acetylcholinesterase and peroxynitrite scavenging activity are seen similarly with three alkaloids. Regarding the aldose reductase inhibitory activities, hydroxy radical scavenging activities and H , K -ATPase inhibitory activities, coptisine exhibits more potent activity than berberine and palmatine. Previous our study has also demonstrated that coptisine is much more potent than berberine in suppressing proliferation of vascular smooth muscle cells (VSMCs), while palmatine failed to show any inhibitory activity. Taken together, the biological activity of these three alkaloids is unlikely to be completely explained by only the slight difference in hydrophobicity based on their structures. Rather, the characteristic structures of each alkaloid appear to be crucial to their respective activities. P-glycoprotein/MDR1, a 170-kDa membrane protein encoded by the ABCB1/MDR1 gene, was the first ATP-binding cassette (ABC) transporter to be identified and has become the most studied gene in the field of multidrug resistance (MDR). Immunohistological studies show that MDR1 highly expresses in specialized epithelial cells with secretory/excretory functions such as epithelial cells lining the gastrointestinal tract and kidney and in endothelial cells of capillary blood vessels at blood-brain and other blood-tissue barrier sites. The expression pattern of MDR1 suggests that its major physiological role is to serve as a barrier to entry of xenobiotics including hydrophobic and amphipathic drugs into body, to remove xenobiotics from the circulation once they have entered, and to keep drugs from leaving the circulation into tissues that are especially sensitive to their toxicities. Furthermore, MDR1 is highly expressed in drug-resistant cancer cells, especially cancer cells derived from cells that normally express MDR1. Since MDR1 overexpression is broadly correlated with drug resistance in many different forms of cancer, effective regulation of MDR has been a long-term objective for improving the efficacy of April 2010 677