Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor.

Article Details

Citation

Usui T, Saitoh Y, Komada F

Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor.

Biol Pharm Bull. 2003 Apr;26(4):510-7. doi: 10.1248/bpb.26.510.

PubMed ID
12673034 [ View in PubMed
]
Abstract

The cytochrome P-450 3A (CYP3A) enzyme family is responsible for most of the drug metabolism in the human liver. In this study, we demonstrated the inductive effects of phenobarbital, rifampicin, carbamazepine, phenytoin, prednisolone, ciclosporin and clotrimazole on CYP3A4, CYP3A5 and CYP3A7 mRNA expression, and established the relationship between the expression of human glucocorticoid receptor alpha (hGR) mRNA and the induction of CYP3A4 mRNA in cultured HepG2 cells by reverse transcription polymerase chain reaction (RT-PCR). Treatment with prednisolone, rifampicin and carbamazepine rapidly induced the level of CYP3A4 mRNA expression by 3- to 6-fold. However, phenytoin and phenobarbital gradually induced CYP3A4 mRNA level by 3 to 4-fold. The induction of CYP3A4 mRNA expression by clotrimazole and ciclosporin was negligible. Treatment with phenytoin, rifampicin, carbamazepine and ciclosporin induced approximately 2-fold increases in the expression of CYP3A5 mRNA, although prednisolone, phenytoin and clotrimazole had no effect. Treatment with rifampicin, phenytoin, clotrimazole and ciclosporin resulted in approximately a 2-fold induction of the CYP3A7 mRNA level. Treatment with rifampicin and ciclosporin induced the expression of hGRalpha mRNA significantly in comparison with controls, although the induction of hGRalpha mRNA following treatment with other drugs was negligible. In cluster analysis, the induced level of CYP3A4, CYP3A5, CYP3A7 and hGRalpha mRNA by these drugs could be classified into four major clusters. This suggested that each cluster might be associated with different mechanism(s) of induction by these drugs. Furthermore, we studied the associations between the expression of hGRalpha mRNA and the induced level of CYP3A4 mRNA by prednisolone and ciclosporin. Treatment with both prednisolone and ciclosporin showed synergistic effects on induction of CYP3A4 mRNA and, following treatment with both drugs, the expression level of CYP3A4 mRNA was 2-fold greater compared with prednisolone alone after the fifth day. Positive correlations were observed between the levels of hGRalpha mRNA expression and those of CYP3A4 mRNA. This observation shows that the regulation of CYP3A4 gene expression was hGRalpha-dependent and that ciclosporin may function as a regulator of expression via hGRalpha.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
BudesonideCytochrome P450 3A4ProteinHumans
No
Substrate
Inducer
Details
Clobetasol propionateCytochrome P450 3A4ProteinHumans
No
Substrate
Inducer
Details
ClotrimazoleCytochrome P450 3A7ProteinHumans
Unknown
Inducer
Details
FlunisolideCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
MethylprednisoloneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
PhenytoinCytochrome P450 3A5ProteinHumans
No
Substrate
Inducer
Details
PhenytoinCytochrome P450 3A7ProteinHumans
Unknown
Substrate
Inducer
Details
PrednisoloneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Prednisolone acetateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Prednisolone phosphateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
PrednisoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
RifampicinCytochrome P450 3A7ProteinHumans
Unknown
Inducer
Details
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
CarbamazepineApproved InvestigationalCYP3A41576
upregulated
Carbamazepine results in increased expression of CYP3A4 mRNA7q22.1
CarbamazepineApproved InvestigationalCYP3A51577
upregulated
Carbamazepine results in increased expression of CYP3A5 mRNA7q22.1
ClotrimazoleApproved Vet ApprovedCYP3A41576
upregulated
Clotrimazole results in increased expression of CYP3A4 mRNA7q22.1
ClotrimazoleApproved Vet ApprovedCYP3A71551
upregulated
Clotrimazole results in increased expression of CYP3A7 mRNA7q22.1
CyclosporineApproved Investigational Vet ApprovedCYP3A41576
upregulated
Cyclosporine results in increased expression of CYP3A4 mRNA7q22.1
CyclosporineApproved Investigational Vet ApprovedCYP3A51577
upregulated
Cyclosporine results in increased expression of CYP3A5 mRNA7q22.1
CyclosporineApproved Investigational Vet ApprovedCYP3A71551
upregulated
Cyclosporine results in increased expression of CYP3A7 mRNA7q22.1
CyclosporineApproved Investigational Vet ApprovedNR3C12908
upregulated
Cyclosporine results in increased expression of NR3C1 mRNA5q31.3
PhenobarbitalApproved InvestigationalCYP3A41576
upregulated
Phenobarbital results in increased expression of CYP3A4 mRNA7q22.1
PhenytoinApproved Vet ApprovedCYP3A41576
upregulated
Phenytoin results in increased expression of CYP3A4 mRNA7q22.1
PhenytoinApproved Vet ApprovedCYP3A51577
upregulated
Phenytoin results in increased expression of CYP3A5 mRNA7q22.1
PhenytoinApproved Vet ApprovedCYP3A71551
upregulated
Phenytoin results in increased expression of CYP3A7 mRNA7q22.1
PrednisoloneApproved Vet ApprovedCYP3A41576
upregulated
Prednisolone results in increased expression of CYP3A4 mRNA7q22.1
RifampicinApprovedCYP3A41576
upregulated
Rifampin results in increased expression of CYP3A4 mRNA7q22.1
RifampicinApprovedCYP3A51577
upregulated
Rifampin results in increased expression of CYP3A5 mRNA7q22.1
RifampicinApprovedCYP3A71551
upregulated
Rifampin results in increased expression of CYP3A7 mRNA7q22.1
RifampicinApprovedNR3C12908
upregulated
Rifampin results in increased expression of NR3C1 mRNA5q31.3