Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog

被引:167
作者
Lu, C [1 ]
Li, AP [1 ]
机构
[1] In Vitro Technol Inc, Baltimore, MD 20227 USA
关键词
human hepatocytes; rat hepatocytes; monkey hepatocytes; minipig hepatocytes; dog hepatocytes; enzyme induction; cytochromes P450; drug-drug interactions; species differences; in vitro metabolism;
D O I
10.1016/S0009-2797(01)00162-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Induction of P450 isoforms 1A (CYP1A) and 3A (CYP3A) by model inducers dexamethasone, omeprazole and rifampin was evaluated in primary cultured hepatocytes from man and laboratory animals. Inducer-specific species-differences were observed. Results with human hepatocytes from six human donors consistently show that both rifampin and dexamethasone were inducers of CYP3A activity (measured as testosterone 6 beta -hydroxylase activity), with rifampin being more potent. Conversely, in rat hepatocytes, dexamethasone was a potent CYP3A inducer while rifampin was not an inducer. Rifampin but not dexamethasone induced CYP3A in minipig and beagle dog hepatocytes. Omeprazole was a potent inducer of CYP1A activity (measured as ethoxyresorufin-O-deethylase activity) in human, beagle dog and minipig hepatocytes, and not an inducer in rat hepatocytes. The species-differences observed suggest that human hepatocytes represent the most appropriate preclinical experimental system for the evaluation of P450 induction in human. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:271 / 281
页数:11
相关论文
共 20 条
  • [1] INDUCTION AND AUTOINDUCTION PROPERTIES OF RIFAMYCIN DERIVATIVES - A REVIEW OF ANIMAL AND HUMAN STUDIES
    BENEDETTI, MS
    DOSTERT, P
    [J]. ENVIRONMENTAL HEALTH PERSPECTIVES, 1994, 102 : 101 - 105
  • [2] BISSELL DM, 1990, MOL BIOL MED, V7, P187
  • [3] Analysis of cytochrome P450 and phase II conjugating enzyme expression in adult male rat hepatocytes
    Davila, JC
    Morris, DL
    [J]. IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL, 1999, 35 (03) : 120 - 130
  • [4] OMEPRAZOLE IS AN ARYL HYDROCARBON-LIKE INDUCER OF HUMAN HEPATIC CYTOCHROME-P450
    DIAZ, D
    FABRE, I
    DAUJAT, M
    SAINTAUBERT, B
    BORIES, P
    MICHEL, H
    MAUREL, P
    [J]. GASTROENTEROLOGY, 1990, 99 (03) : 737 - 747
  • [5] EFFECT OF XENOBIOTICS ON MONOOXYGENASE ACTIVITIES IN CULTURED HUMAN HEPATOCYTES
    DONATO, MT
    GOMEZLECHON, MJ
    CASTELL, JV
    [J]. BIOCHEMICAL PHARMACOLOGY, 1990, 39 (08) : 1321 - 1326
  • [6] HARAUCHI T, 1994, BIOL PHARM BULL, V17, P658
  • [7] Herbert Mary F., 1992, Clinical Pharmacology and Therapeutics, V52, P453
  • [8] Hosagrahara VP, 1999, DRUG METAB DISPOS, V27, P1512
  • [9] KENO Y, 1997, IN VITRO CELL DEV, V33, P467
  • [10] Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin
    Li, AP
    Reith, MK
    Rasmussen, A
    Gorski, JC
    Hall, SD
    Xu, L
    Kaminski, DL
    Cheng, LK
    [J]. CHEMICO-BIOLOGICAL INTERACTIONS, 1997, 107 (1-2) : 17 - 30