title: Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes.
abstract: 1. Blood levels of S-warfarin have been reported to be increased by concomitant administration of metronidazole (MTZ), an antiprotozoal imidazole derivative. 2. To elucidate the mechanism of this interaction and to identify other possible drug-drug interactions, we conducted an in vitro study with the human hepatoma HepaRG cells and cryopreserved human hepatocytes on the ability of MTZ to reduce the expression of cytochrome P450 (CYP) as well as nuclear receptors that regulate the expression of these enzymes. 3. HepaRG cells and cryopreserved human hepatocytes were treated with MTZ (20 to 500 µM) and were then analyzed by real-time RT-PCR to determine mRNA levels of drug-metabolizing enzymes and nuclear receptors. 4. In both cells, the expressions of CYP2C8, CYP2C9, CYP3A4 and constitutive androstane receptor (CAR) were decreased by MTZ treatment. Particularly, in HepaRG cells, their mRNA levels were decreased by MTZ treatment in a concentration-dependent manner. 5. Our findings suggest that the interaction between MTZ and S-warfarin may be due to the MTZ-induced down-regulation of CYP2C9, the primary enzyme responsible for S-warfarin hydroxylation, and CAR, which regulates CYP2C9 expression. We also found that MTZ use may alter the disposition of drugs metabolized by the CYP isozymes investigated.
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University , Tokyo , Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kudo
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Endo
authors.forename: Rina
authors.initials: R
authors.lastname: Taguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Yatsu
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ito
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014019:Tissue Donors; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D008795:Metronidazole; D003577:Cytochrome P-450 Enzyme System
keywords: Cryopreserved human hepatocytes; Hepa RG cells; cytochrome P450; drug-drug interactions; metronidazole; nuclear receptors