Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor.
Article Details
- CitationCopy to clipboard
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
Drug Enzyme Kind Organism Pharmacological Action Actions Budesonide Cytochrome P450 3A4 Protein Humans NoSubstrateInducerDetails Clobetasol propionate Cytochrome P450 3A4 Protein Humans NoSubstrateInducerDetails Clotrimazole Cytochrome P450 3A7 Protein Humans UnknownInducerDetails Flunisolide Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Methylprednisolone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Phenytoin Cytochrome P450 3A5 Protein Humans NoSubstrateInducerDetails Phenytoin Cytochrome P450 3A7 Protein Humans NoSubstrateInducerDetails Prednisolone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Prednisolone acetate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Prednisolone phosphate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Prednisone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Rifampicin Cytochrome P450 3A7 Protein Humans UnknownInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Carbamazepine Approved Investigational CYP3A4 1576 upregulated Carbamazepine results in increased expression of CYP3A4 mRNA 7q22.1 Carbamazepine Approved Investigational CYP3A5 1577 upregulated Carbamazepine results in increased expression of CYP3A5 mRNA 7q22.1 Clotrimazole Approved Vet Approved CYP3A4 1576 upregulated Clotrimazole results in increased expression of CYP3A4 mRNA 7q22.1 Clotrimazole Approved Vet Approved CYP3A7 1551 upregulated Clotrimazole results in increased expression of CYP3A7 mRNA 7q22.1 Cyclosporine Approved Investigational Vet Approved CYP3A4 1576 upregulated Cyclosporine results in increased expression of CYP3A4 mRNA 7q22.1 Cyclosporine Approved Investigational Vet Approved CYP3A5 1577 upregulated Cyclosporine results in increased expression of CYP3A5 mRNA 7q22.1 Cyclosporine Approved Investigational Vet Approved CYP3A7 1551 upregulated Cyclosporine results in increased expression of CYP3A7 mRNA 7q22.1 Cyclosporine Approved Investigational Vet Approved NR3C1 2908 upregulated Cyclosporine results in increased expression of NR3C1 mRNA 5q31.3 Phenobarbital Approved Investigational CYP3A4 1576 upregulated Phenobarbital results in increased expression of CYP3A4 mRNA 7q22.1 Phenytoin Approved Vet Approved CYP3A4 1576 upregulated Phenytoin results in increased expression of CYP3A4 mRNA 7q22.1 Phenytoin Approved Vet Approved CYP3A5 1577 upregulated Phenytoin results in increased expression of CYP3A5 mRNA 7q22.1 Phenytoin Approved Vet Approved CYP3A7 1551 upregulated Phenytoin results in increased expression of CYP3A7 mRNA 7q22.1 Prednisolone Approved Vet Approved CYP3A4 1576 upregulated Prednisolone results in increased expression of CYP3A4 mRNA 7q22.1 Rifampicin Approved CYP3A4 1576 upregulated Rifampin results in increased expression of CYP3A4 mRNA 7q22.1 Rifampicin Approved CYP3A5 1577 upregulated Rifampin results in increased expression of CYP3A5 mRNA 7q22.1 Rifampicin Approved CYP3A7 1551 upregulated Rifampin results in increased expression of CYP3A7 mRNA 7q22.1 Rifampicin Approved NR3C1 2908 upregulated Rifampin results in increased expression of NR3C1 mRNA 5q31.3