Species differences in the response of liver drug-metabolizing enzymes to (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949) in vivo and in vitro.

Details

Serval ID
serval:BIB_389D69AD3FDA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Species differences in the response of liver drug-metabolizing enzymes to (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949) in vivo and in vitro.
Journal
Drug Metabolism and Disposition
Author(s)
Richert L., Tuschl G., Viollon-Abadie C., Blanchard N., Bonet A., Heyd B., Halkic N., Wimmer E., Dolgos H., Mueller S.O.
ISSN
0090-9556
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
36
Number
4
Pages
702-714
Language
english
Abstract
Induction of drug-metabolizing enzymes (DMEs) is highly species-specific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species specificity of the antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPARalpha target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPARalpha agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPARalpha agonists in monkeys and humans.
Keywords
Aged, Animals, Butyric Acid/administration & dosage, Butyric Acid/chemistry, Cells, Cultured, Cytochrome P-450 Enzyme System/genetics, Cytochrome P-450 Enzyme System/metabolism, Female, Gene Expression Regulation, Enzymologic/drug effects, Humans, Liver/drug effects, Liver/enzymology, Macaca fascicularis, Male, Middle Aged, PPAR alpha/genetics, PPAR alpha/metabolism, Rats, Rats, Wistar, Species Specificity
Pubmed
Web of science
Create date
13/10/2009 11:53
Last modification date
20/08/2019 13:27
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