title: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes.
abstract: Cultured human hepatocytes are a valuable in vitro system for evaluating new molecular entities as inducers of cytochrome P450 (P450) enzymes. The present study summarizes data obtained from 62 preparations of cultured human hepatocytes that were treated with vehicles (saline or dimethylsulfoxide, 0.1%), beta-naphthoflavone (33 microM), phenobarbital (100 or 250 microM), isoniazid (100 microM) and/or rifampin (20 or 50 microM), and examined for the expression of P450 enzymes based on microsomal activity toward marker substrates, or in the case of CYP2C8, the level of immunoreactive protein. The results show that CYP1A2 activity was markedly induced by beta-naphthoflavone (on average 13-fold, n = 28 preparations), and weakly induced by phenobarbital (1.9-fold, n = 25) and rifampin (2.3-fold, n = 22); CYP2A6 activity tended to be increased with phenobarbital (n = 7) and rifampin (n = 3) treatments, but the effects were not statistically significant; CYP2B6 was induced by phenobarbital (6.5-fold, n = 13) and rifampin (13-fold, n = 14); CYP2C8 was induced by phenobarbital (4.0-fold, n = 4) and rifampin (5.2-fold, n = 4); CYP2C9 was induced by phenobarbital (1.8-fold, n = 14) and rifampin (3.5-fold, n = 10); CYP2C19 was markedly induced by rifampin (37-fold, n = 10), but relatively modestly by phenobarbital (7-fold, n = 9); CYP2D6 was not significantly induced by phenobarbital (n = 5) or rifampin (n = 5); CYP2E1 was induced by phenobarbital (1.7-fold, n = 5), rifampin (2.2-fold, n = 5), and isoniazid (2.3-fold, n = 5); and, CYP3A4 was induced by phenobarbital (3.3-fold, n = 42) and rifampin (10-fold, n = 61), but not by beta-naphthoflavone. Based on these observations, we generalize that beta-naphthoflavone induces CYP1A2 and isoniazid induces CYP2E1, whereas rifampin and, to a lesser extent phenobarbital, tend to significantly and consistently induce enzymes of the CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A subfamilies but not the 2D subfamily.
authors.affiliation: XenoTech, LLC, 16825 West 116th Street, Lenexa, KS 66219, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Carroll
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.forename: L Alayne
authors.initials: LA
authors.lastname: Burton
authors.forename: Linda A
authors.initials: LA
authors.lastname: Krueger
authors.forename: April D
authors.initials: AD
authors.lastname: Downey
authors.forename: Maciej
authors.initials: M
authors.lastname: Czerwinski
authors.forename: Jameson
authors.initials: J
authors.lastname: Forster
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: Liang-Shang
authors.initials: LS
authors.lastname: Gan
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
authors.forename: Karl
authors.initials: K
authors.lastname: Zech
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
authors.forename: Patrick
authors.initials: P
authors.lastname: Koch
authors.forename: Lida
authors.initials: L
authors.lastname: Antonian
authors.forename: Greg
authors.initials: G
authors.lastname: Wagner
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Andrew
authors.initials: A
authors.lastname: Parkinson
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000145:classification / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D019324:beta-Naphthoflavone / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D007538:Isoniazid; D012293:Rifampin; D010634:Phenobarbital