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  • In vitro tool for P450 induction screening
  • High levels of drug-metabolizing enzymes (Phase I and II)
  • Intact nuclear receptor pathways (PXR & CAR)
  • Active drug transporters

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A unique in vitro system for ADME/Tox studies

HepaRG™ cells are terminally differentiated hepatic cells derived from a human hepatic progenitor cell line that retains many characteristics of primary human hepatocytes. HepaRG™ cells are provided in a convenient cryopreserved, single use format. For scientists who need reproducible metabolism data, HepaRG™ cells are an in vitro tool that provides reproducible results in a metabolically complete and scalable system.

HepaRG™ cells exhibit many characteristics of primary human hepatocytes, including morphology and expression of key metabolic enzymes, nuclear receptors, and drug transporters. Unlike HepG2 and Fa2N-4 cells, HepaRG™ cells have high P450 activity and complete expression of all nuclear receptors.

Infinitely reproducible

HepaRG™ cells lack donor variability, and lot sizes are not limited by donor tissue availability, ensuring an indefinite and consistent supply of cells. Thus experimental results can be infinitely reproduced.  (Note: The cells provided by Life Technologies are terminally differentiated and cryopreserved.) 

  
  

Induction Screening

P450 enzymes can be induced as a result of drug exposure, which may cause increased formation of toxic metabolites and/or decreased systemic levels of a co-administered drug potentially resulting in drug toxicity or decreased drug efficacy. The use of primary human hepatocytes in screening applications is limited by tissue availability, donor variability, cost, and a relative short culture lifespan. The use of HepaRG™ cells solves these limitations without sacrificing critical hepatocyte traits such as drug metabolizing enzyme expression, functional transport proteins, and expression of key nuclear receptor pathways. HepaRG™ cells respond to prototypical P450 inducers such as omeprazole (OMP), phenobarbital (PB), and rifampicin (RIF) demonstrating the utility of this cell system in the evaluation of in vitro enzyme induction (Figure 1).

  
Figure 1. Induction of CYP1A2, CYP2B6, and CYP3A4 enzyme activity (A) and mRNA expression (B) in HepaRG™ cells or primary human hepatocytes (PHH) treated with omeprazole (OMP), phenobarbital (PB), or rifampicin (RIF) for 72 hr in culture. Box and whisker plots (box = 25th to 75th percentile, line within box = median, whiskers = extreme values observed) were generated using data from multiple PHH preparations, illustrating the large donor-to-donor variability observed in PHH. HepaRG™ data (activity and mRNA) for CYP1A2, CYP2B6, and CYP3A4 are denoted as red diamonds and were generated from three separate vials.

Metabolism

Estimates of in vivo metabolic drug clearance can be determined from in vitro metabolism kinetic data. Metabolic stability studies are typically performed to estimate a drug candidate’s metabolic half-life and intrinsic clearance rates, which are major determinants of in vivo drug efficacy. Compounds with short half-lives may require multiple doses to maintain effective plasma levels, whereas compounds with slower elimination kinetics require fewer doses. Unlike other cell lines (e.g., HepG2 and Fa2N-4) HepaRG™ cells have expression levels of key metabolic enzymes and nuclear receptors consistent with levels observed in PHH, and therefore, are more suitable to assess the metabolic stability of candidate compounds (Figure 2).

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Figure 2. Intrinsic clearance of the reference drugs aminodarone, carbamezepine, clozapine, diclofenac, dextromethorphan, lovastatin, methotrexate, rifampicine, tacrine, troglitazone, and verapamil in cultures of primary human hepatocytes (PHH, n=6) and HepaRG™ cells (n = 2).  Results are shown as means + SD [2].

Toxicity

The liver plays a central role in metabolizing and eliminating xenobiotics and as a result is susceptible to injury from drug toxicity. Liver toxicity has led to withdrawal or severe use limitations of marketed drugs and is a major problem in drug development. HepaRG™ cells are a metabolically competent system and tolerant of long culture periods (i.e. ≥22 days).  In addition, they are well suited for in vitro determinations of acute and chronic toxicity resulting from intrinsic and/or metabolism-based mechanisms (Figures 3 and 4).

 

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Figure 3. HepaRG™ cell viability after 24 hr and 72 hr treatment with metabolism-dependent toxicants [3].
      

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Figure 4. Comparative cytotoxicity of aflatoxin B1 in HepG2 and HepaRG™ cells after a 3-day treatment. Cell viability was estimated using a standard MTT test. The values were normalized to untreated cells and expressed as means ± SD (n = 3 cultures) [4].

Transporters

Transporters often work together with drug-metabolizing enzymes in drug absorption and elimination, resulting in altered drug efficacy and adverse drug effects. HepaRG™ cells have superior expression levels of key uptake and efflux transporters compared to other cell lines, and expression levels closely resembling those of human hepatocytes (Figures 5 and 6).

 

Figure 5. Uptake transporter gene expression, HepaRG™ and HepG2 cells vs. PHH [5].
      
Figure 6. Efflux transporter gene expression, HepaRG™ and HepG2 cells vs. PHH [5].
 

 

Ordering Information

Sku Name Size Price Qty
HPRG620 HepaRG™ Maintenance/Metabolism Medium Supplement 1 bottle USD 70.50
HPRG630 HepaRG™ Tox Medium Supplement 1 bottle USD 70.00
HPRG640 HepaRG™ Induction Medium Supplement 1 bottle USD 70.50
HPRG650 HepaRG™ Serum-free Induction Medium Supplement 1 bottle USD 70.50
HPRG670 HepaRG™ Thaw, Plate, & General Purpose Medium Supplement 1 bottle USD 74.20
HPRG720 HepaRG™ Maintenance/Metabolism Medium Supplement (5X) 1 bottle USD 207.00
HPRG730 HepaRG™ Tox Medium Supplement (5X) 1 bottle USD 205.00
HPRG740 HepaRG™ Induction Medium Supplement (5X) 1 bottle USD 207.00
HPRG750 HepaRG™ Serum-free Induction Medium Supplement (5X) 1 bottle USD 207.00
HPRG770 HepaRG™ Thaw, Plate & General Purpose Medium Supplement (5X) 1 bottle USD 207.00
A1217601 William's E Medium, no phenol red 500 mL USD 36.00
A1142802 Collagen I, Coated Plate, 24 well 5 plates USD 63.00
A1142803 Collagen I, Coated Plate, 96 well 5 plates USD 67.00
35050061 GlutaMAX™ Supplement 100 mL USD 30.40
HPRGC10 HepaRG™ Cells, Cryopreserved 10 x 106 cells USD 584.00

References

  1. Aninat C et al. (2008) Crit Care Med 36:848–854.
  2. Lübberstedt M et al. (2011) J Pharmacol Toxicol Methods 63:59–68.
  3. Aninat C et al. (2006) Drug Metab Dispos 34:75–83.
  4. Guillouzo A et al. (2007) Chem Biol Interact 168:66–73.
  5. Le Vee M et al. (2006) Eur J Pharm Sci 28:109–117.

 

HepaRG™ is a trademark of BioPredic International.
For research use only. Not intended for any animal or human therapeutic or diagnostic use.

Limited Use License
HepaRG™ cells are patented and their use is strictly limited; consider the cells as a single-use, disposable product that must be destroyed upon conclusion of a study or experiment. Propagating, reproducing, cloning, subcloning or any other use of the cells following the conclusion of a study is prohibited. Use of the cells to produce or manufacture commercial products for general sale or for use in the manufacture of products intended for general sale is prohibited. Transfer of the cells to anyone not employed within the same organization, whether for financial benefit or not, is also prohibited.