Cytochrome P450 (CYP) induction plays an important role in the pharmacokinetics of a drug and may potentially affect drug efficacy by reducing plasma half-life, or drug toxicity if elevated levels of toxic metabolites are formed. These effects are usually observed when a drug has an effect on a co-administered medication. Transcriptional gene activation mediated by nuclear receptors such as the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), is the most common mechanism of CYP induction. These receptors are directly related to the expression of CYP1A2 (AhR), CYP2B6 (CAR) and CYP3A4 (PXR). Therefore, receptor activation can serve as an early indicator of potential changes in CYP enzyme expression. A less common mechanism for CYP induction is that certain drugs don’t necessarily stimulate the expression of CYP enzymes, but rather, slow down CYP protein degradation.
The use of human hepatocytes is considered to be the "gold standard" for assessing whether a compound induces CYP isoform expression. Human hepatocytes are used not only to determine whether a compound induces important CYPs, but also to further investigate the mechanisms of induction.
Table 1. Mechanisms of CYP isoform induction.
| CYP | Receptors | Prototypical ligand |
| CYP1A | AhR | TCDD |
| CYP2B6 | hCAR | CITCO |
| CYP3A4 | hPXR | Rifampicin |
| CYP4A | hPPA | Thiazolidinediones |
| CYP7A | FXR/LXR | Bile acids/Oxysterols |
Our CYP induction assays are tailored for cost-efficient simultaneous evaluation of higher number of compounds. Each assay delivers CYP induction relative to vehicle control and/or EC50 values, if possible. The induction assays can be used for CYP1A2, CYP2B6 and CYP3A4, other CYPs are available upon request.
Creative Bioarray offers the following study designs:
- Cryopreserved primary human hepatocytes from three donors
- Determination of CYP1A2, CYP2B6, CYP3A4 mRNA expression
- 6 - 8 concentrations of test article
- Vehicle control (test article solvent)
- Negative control for induction (clinical and in vitro non-inducer)
- Multiple positive controls (prototypical inducers)
- Perform media analysis with multiple time point collections
- EC50 / Emax data
- Complete submission of quality reports
Our Methodologies
- Immunoblotting for CYPs, phase II enzymes and transporters
- mRNA analysis including RT-PCR, northern blotting and gene arrays
- Reporter gene assays and nuclear receptor binding assays
- Catalytic/marker substrate assays
- In silico methods (prediction of PXR ligands from chemical structure)
Learn about the potential drug-drug interactions of your compounds by using our CYP induction assay. Creative Bioarray delivers consistent, high-quality data with the flexibility to adapt protocols based on specific customer requirements.
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