Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes.

Article Details

Citation

Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A

Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes.

Drug Metab Dispos. 2003 Apr;31(4):421-31. doi: 10.1124/dmd.31.4.421.

PubMed ID
12642468 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
IsoniazidCytochrome P450 2E1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
PhenobarbitalCytochrome P450 1A2ProteinHumans
No
Inducer
Details
PhenobarbitalCytochrome P450 2A6ProteinHumans
Unknown
Inducer
Details
PhenobarbitalCytochrome P450 2B6ProteinHumans
Unknown
Inducer
Details
PhenobarbitalCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inducer
Details
PhenobarbitalCytochrome P450 2E1ProteinHumans
Unknown
Substrate
Inducer
Details
RifampicinCytochrome P450 2C8ProteinHumans
Unknown
Inhibitor
Inducer
Details
Drug Interactions
DrugsInteraction