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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/32733
Title: Interactions of sesquiterpenes zederone and germacrone with the human cytochrome P450 system
Authors: Prapapan Pimkaew
Jenni Küblbeck
Aleksanteri Petsalo
Jouni Jukka
Apichart Suksamrarn
Risto Juvonen
Seppo Auriola
Pawinee Piyachaturawat
Paavo Honkakoski
Mahidol University
Ita-Suomen yliopisto
Ramkhamhaeng University
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Sep-2013
Citation: Toxicology in Vitro. Vol.27, No.6 (2013), 2005-2012
Abstract: Misclassification of Curcuma species (family Zingiberaceae) may lead to unwanted human exposure to Curcuma elata sesquiterpenes zederone and germacrone which have caused hepatotoxicity and changes in CYP expression in laboratory animals. We investigated how these compounds interact with the human cytochrome P450 (CYP) system, in order to evaluate their potential for human liver toxicity and herb-drug interactions. We found that both sesquiterpenes (1-30μM) greatly induced expression of CYP2B6 and CYP3A4 but not CYP1A2 mRNAs in human primary hepatocytes (HPHs). This induction profile correlated with activation of constitutive androstane and pregnane X receptors. Cytotoxicity was also observed in exposed HPHs. CYP inhibition studies with pooled human liver microsomes (HLMs) indicated that zederone and germacrone moderately inhibited CYP2B6 and CYP3A4 activities in vitro, with IC50values below 10μM. When zederone was incubated with HLMs and NADPH, one di-epoxide metabolite was formed and by using glutathione trapping, five epoxide-derived conjugates were detected. Germacrone produced two oxidized metabolites and four glutathione conjugates. The results suggest that enzymes in HLMs convert sesquiterpenes into reactive, electrophilic compounds which may be causative for the reported liver injuries. These findings provide insight on the safety and drug-herb interactions of the Curcuma species. © 2013 Elsevier Ltd.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84881240685&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/32733
ISSN: 18793177
08872333
Appears in Collections:Scopus 2011-2015

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