Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.Malaria, a parasitic infection by protozoans, is one of the most threatening human infections worldwide. Among the four human malaria parasites, Plasmodium falciparum causes the majority of all severe cases and deaths. Because of the extensive use of monotherapy in the past, this parasite has rapidly developed resistance to several commonly used and cost-effective antimalarial drugs, including chloroquine, sulfadoxine-pyrimethamine, and mefloquine, in many malaria-affected areas (White, 2004). Spread of resistant parasites is regarded to be a major contributor to the global resurgence of malaria in the last decades. Today, artemisinin drugs represent the only therapeutically used antimalarial drug class to which resistance has not yet been developed. Therefore, these drugs are increasingly used in the treatment of drug-resistant falciparum malaria, especially in combination therapy with a second antimalarial drug (White, 2004).Artemisinin, a sesquiterpene lactone endoperoxide, wasThis work was supported by Deutsche Forschungsgemeinschaft Grant Bu 1249/1-2, 3, and the Robert Bosch Foundation (Germany).Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.104.009019.ABBREVIATIONS: P450, cytochrome P450; PXR, pregnane X receptor; CAR, constitutive androstane receptor; MDR, multidrug resistance; CITCO,

The results show that primary human liver cells obtained from discarded donor organs recover and can be maintained in bioreactors for clinical liver support therapy. In addition, initial observations on adult liver stem-cell culture in bioreactors are presented.

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Appropriate software tools may improve communication and ease access to knowledge for research groups. A weblog is a website which contains periodic, chronologically ordered posts on a common webpage, whereas a wiki is hypertext-based collaborative software that enables documents to be authored collectively using a web browser. Although not primarily intended for use as an intranet-based collaborative knowledge warehouse, both blogs and wikis have the potential to offer all the features of complex and expensive IT solutions. These tools enable the team members to share knowledge simply and quickly-the collective knowledge base of the group can be efficiently managed and navigated.