BACKGROUND AND PURPOSE The expression of P‐glycoprotein (P‐gp), encoded by the multidrug resistance 1 (MDR1) gene, is associated with the emergence of the MDR phenotype in cancer cells. We investigated whether metformin (1,1‐dimethylbiguanide hydrochloride) down‐regulates MDR1 expression in MCF‐7/adriamycin (MCF‐7/adr) cells.EXPERIMENTAL APPROACH MCF‐7 and MCF‐7/adr cells were incubated with metformin and changes in P‐gp expression were determined at the mRNA, protein and functional level. Transient transfection assays were performed to assess its gene promoter activities, and immunoblot analysis to study its molecular mechanisms of action.KEY RESULTS Metformin significantly inhibited MDR1 expression by blocking MDR1 gene transcription. Metformin also significantly increased the intracellular accumulation of the fluorescent P‐gp substrate rhodamine‐123. Nuclear factor‐κB (NF‐κB) activity and the level of IκB degradation were reduced by metformin treatment. Moreover, transduction of MCF‐7/adr cells with the p65 subunit of NF‐κB induced MDR1 promoter activity and expression, and this effect was attenuated by metformin. The suppression of MDR1 promoter activity and protein expression was mediated through metformin‐induced activation of AMP‐activated protein kinase (AMPK). Small interfering RNA methods confirmed that reduction of AMPK levels attenuates the inhibition of MDR1 activation associated with metformin exposure. Furthermore, the inhibitory effects of metformin on MDR1 expression and cAMP‐responsive element binding protein (CREB) phosphorylation were reversed by overexpression of a dominant‐negative mutant of AMPK.CONCLUSIONS AND IMPLICATIONS These results suggest that metformin activates AMPK and suppresses MDR1 expression in MCF‐7/adr cells by inhibiting the activation of NF‐κB and CREB. This study reveals a novel function of metformin as an anticancer agent.

Since many glycoside compounds in natural products are hydrolyzed by intestinal microbiota when administered orally, it is of interest to know whether their pharmacological effects are derived from the glycoside itself or from the aglycone form in vivo. An interesting example is baicalin versus baicalein, the aglycone of baicalin, which is contained in some herbs from Labiatae including Scutellaria baicalensis Georgi and Scutellaria lateriflora Linne. The herbs have been extensively used for treatment of inflammatory diseases in Asia. Although there have been numerous reports regarding the pharmacological effects of baicalin and baicalein in vivo and in vitro, some reports indicated that the glycoside form would hardly be absorbed in the intestine and that it should be hydrolyzed to baicalein in advance for absorption. Therefore, the role of metabolism by intestinal microbiota should also be considered in the metabolism of baicalin. In addition, baicalin contains a glucuronide moiety in its structure, by which baicalin and baicalein show complex pharmacokinetic behaviors, due to the interconversion between them by phase II enzymes in the body. Recently, concerns about drug interaction with baicalin and/or baicalein have been raised, because of the co-administration of Scutellaria species with certain drugs. Herein, we reviewed the role of intestinal microbiota in pharmacokinetic characteristics of baicalin and baicalein, with regards to their pharmacological and toxicological effects.

Introduction: Numerous drugs and toxicants must be metabolized to an active form. Metabolic activation by host tissues, such as the liver, has been well studied. However, drug and toxicant metabolism by the intestinal microbiota is an unexplored, but essential, field of study in pharmacology and toxicology. The taxonomic diversity and sheer numbers of the intestinal microbiota, and their capacity to metabolize xenobiotics, underscore the importance of this mode of metabolism. Areas covered: Metabolism by the intestinal microbiota has focused on the natural products of glycosides hydrolyzed by intestinal microbiota enzymes, but not by host tissues. Metabolism of synthetic drugs by the intestinal microbiota has been less-intensively investigated. This review provides an overview of xenobiotic metabolism by the intestinal microbiota of both natural products and synthetic drugs. Expert opinion: Metabolism by the intestinal microbiota might result in a different metabolite profile than that produced by host tissues. This could potentially result in either activation or inactivation of the pharmacological and/or toxicological actions of the compound in question. The contribution of the intestinal microbiota to drug metabolism remains relatively unexplored. Therefore, studies of xenobiotic metabolism by the intestinal microbiota need to be included in new drug development as well as classical studies of host tissue metabolism.