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Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms

2012-10Journal article Open access
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dc.contributor.authorBurk, O.
dc.contributor.authorPiedade, R.
dc.contributor.authorGhebreghiorghis, L.
dc.contributor.authorFait, J. T.
dc.contributor.authorNussler, A. K.
dc.contributor.authorGil, J. P.
dc.contributor.authorWindshuegel, B.
dc.contributor.authorSchwab, M.
dc.date.accessioned2018-12-07T14:58:05Z
dc.date.available2018-12-07T14:58:05Z
dc.date.issued2012-10
dc.description.abstractBACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drugdrug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drugdrug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.
dc.description.sponsorshipGerman Federal Ministry of Education and Research (BMBF) HepatosSys network [0313081B, 0313080F, 0313080I]; Deutsche Forschungsgemeinschaft (Germany) [KE 1629/1-1]; Robert Bosch Foundation, Stuttgart, Germany
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1111/j.1476-5381.2012.02033.x
dc.identifier.issn0007-1188
dc.identifier.urihttp://hdl.handle.net/10400.1/11846
dc.language.isoeng
dc.peerreviewedyes
dc.publisherWiley-Blackwell
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectPregnane-X-receptor
dc.subjectLigand-binding
dc.subjectForce-field
dc.subjectHuman liver
dc.subjectIn-vitro
dc.subjectCar
dc.subjectAntimalarial
dc.subjectInduction
dc.subjectCyp2B6
dc.subjectCytochrome-P450
dc.titleDifferential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage681
oaire.citation.issue3
oaire.citation.startPage666
oaire.citation.titleBritish Journal of Pharmacology
oaire.citation.volume167
person.familyNameNussler
person.familyNameGil
person.givenNameAndreas
person.givenNameJosé Pedro
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-6666-6791
person.identifier.orcid0000-0002-6107-9379
person.identifier.scopus-author-id7201625436
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication4123748b-c9d0-4878-8698-e1316c97aaf7
relation.isAuthorOfPublicationcb728715-0e4c-4ae5-9e21-b6a8f35a8313
relation.isAuthorOfPublication.latestForDiscovery4123748b-c9d0-4878-8698-e1316c97aaf7

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