title: Species-specific activation of nuclear receptors correlates with the response of liver drug metabolizing enzymes to EMD 392949 in vitro.
abstract: We previously reported on the species-specific effects on drug metabolizing enzymes (DME), in particular cytochrome P450-dependent monooxygenases (P450s), by the drug development candidate EMD 392949 (EMD) in vitro and in vivo. Induction of P450s occurs via activation of specific transcription factors such as the arylhydrocarbon receptor (AhR) and the nuclear xenobiotic receptors (NXRs). We analyzed whether the reported species-specific P450 induction by EMD could be related to a specific activation of the CYP1A regulator AhR and the CYP3A regulator pregnane X receptor (PXR) in human and rat cell lines. The human HepG2 and rat H4IIE cell lines exhibited inducibility of CYP1A and 3A and expressed functional AhR as well as PXR. CYP3A was induced by EMD in human HepG2 cells exceeding the level induced by rifampicin, but was not induced in rat H4IIE cells. Regulation of P450s was not related to expression levels of their respective transcription factor, but EMD treatment resulted in a significant reporter gene activation in xenobiotic response enhancer module (XREM)-transfected HepG2 but not H4IIE cells indicating activation of human but not rat PXR. In summary, we showed that the P450 inducing properties of EMD were perfectly reflected by its ability to activate AhR or PXR in a species-specific manner. These findings support the tight correlation of species-specific nuclear receptor activation with P450 induction and foster the use of nuclear receptor activation as a complementary screen to identify cytochrome P450 inducers.
authors.affiliation: Merck KGaA, Merck Serono, Non-Clinical Development, Toxicology, Darmstadt, Germany. stefan.o.mueller@merck.de
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Mueller
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fery
authors.forename: Gregor
authors.initials: G
authors.lastname: Tuschl
authors.forename: Dieter
authors.initials: D
authors.lastname: Schrenk
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014162:Transfection
chemical_list: D002087:Butyrates; D017931:DNA Primers; C547424:EMD 392949; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1