Back to Search
Start Over
Effects of Prototypical Microsomal Enzyme Inducers on Cytochrome P450 Expression in Cultured Human Hepatocytes
- Source :
- Drug Metabolism and Disposition. 31:421-431
- Publication Year :
- 2003
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2003.
-
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.
- Subjects :
- CYP2B6
CYP3A
Blotting, Western
Pharmaceutical Science
Enzyme-Linked Immunosorbent Assay
Biology
Pharmacology
Mixed Function Oxygenases
Cytochrome P-450 CYP2A6
Cytochrome P-450 CYP2C8
Cytochrome P-450 Enzyme System
beta-Naphthoflavone
Cytochrome P-450 CYP1A2
Isoniazid
medicine
Cytochrome P-450 CYP3A
Humans
Enzyme Inhibitors
Enzyme inducer
CYP2A6
Cells, Cultured
CYP3A4
CYP1A2
Oxidoreductases, N-Demethylating
CYP2E1
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2B6
Liver
Enzyme Induction
Phenobarbital
Hepatocytes
biology.protein
Aryl Hydrocarbon Hydroxylases
Rifampin
medicine.drug
Subjects
Details
- ISSN :
- 1521009X and 00909556
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism and Disposition
- Accession number :
- edsair.doi.dedup.....22e9b32e26ca0699a3c57f5f9f45549f