Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450.

Article Details

Citation

Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, Shou M

Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450.

Xenobiotica. 2000 Apr;30(4):327-43.

PubMed ID
10821163 [ View in PubMed
]
Abstract

1. The selectivity of eight chemical inhibitors has been extensively evaluated with 10 cDNA-expressed human cytochrome P450 isoforms (CYP). The results indicate that sulphaphenazole, quinidine and alpha-naphthoflavone are selective inhibitors of CYP2C9 (IC50 = 0.5-0.7 microM), CYP2D6 (0.3-0.4 microM) and CYP1A (0.05-5 microM) respectively on the basis of the IC50, which are much lower than those of other P450 isoforms (> 10-fold). 2. Ketoconazole exhibited potent inhibition of both CYP3A4-catalysed metabolism of phenanthrene, testosterone, diazepam (IC50 = 0.03-0.5 microM) and CYP1A1-catalysed deethylation of 7-ethoxycoumarin (0.33 microM). The selectivity of ketoconazole for other P450s was highly related to the concentration used. 3. Diethyldithiocarbamate, orphenadrine and furafylline were shown separately to be less selective inhibitors of CYP2E1, CYP2B6 and CYP1A isoforms by a broad range of IC50 that overlap those observed with other P450 isoforms. 4. Furafylline, quinidine and alpha-naphthoflavone activated CYP3A4-catalysed phenanthrene metabolism by 1.7-, 2- and 15-fold respectively. 5. The selectivity of orphenadrine and ketoconazole was further examined by using inhibitory monoclonal antibodies (MAb). Inhibitory MAb specific for the individual P450 isoforms may be of greater value than chemical inhibitors.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
KetoconazoleCytochrome P450 1A1ProteinHumans
Unknown
Inhibitor
Inducer
Details
OrphenadrineCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
QuinidineCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
SulfaphenazoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfaphenazoleCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details