title: Interactions of sesquiterpenes zederone and germacrone with the human cytochrome P450 system.
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 (1-30 μM) 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 IC50 values below 10 μM. 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.
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Prapapan
authors.initials: P
authors.lastname: Pimkaew
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Petsalo
authors.forename: Jouni
authors.initials: J
authors.lastname: Jukka
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Risto
authors.initials: R
authors.lastname: Juvonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D030024:Curcuma; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D045788:Sesquiterpenes, Germacrane / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D065607:Cytochrome P-450 Enzyme Inhibitors; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D045788:Sesquiterpenes, Germacrane; C048393:germacrone; D003577:Cytochrome P-450 Enzyme System; C586942:zederone
keywords: 1,4-bis[2-(3,5-dichloropyridyl-oxy)]benzene; 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichloro-benzyl)oxime; ACN; AhR; CAR; CITCO; CYP; Curcuma elata; Cytochrome P450; DMSO; GAPDH; GSH; HLM; HPH; Induction; Inhibition; LDH; MRM; OME; PCN; PHN; PXR; RIF; Sesquiterpenes; TCP; Toxicity; acetonitrile; aryl hydrocarbon receptor; constitutive androstane receptor; cytochrome P450; dimethyl sulfoxide; glutathione (reduced); glyseraldehyde 3-phosphate dehydrogenase; human liver microsomes; human primary hepatocyte; lactate dehydrogenase; multiple reaction monitoring; omeprazole; phenytoin; pregnane X receptor; pregnenolone-16α-carbonitrile; rifampicin