HepaRGTM CYP induction test method augmentation part 1: The GOLIATH Study
Abstract
Cytochrome P450 (CYP) enzymes play a key role in the metabolism of both xenobiotics and endogenous com-pounds, and some CYP isoforms are susceptible to induction and/or inhibition by certain chemicals. As CYP induction/inhibition can significantly alter the in vivo fate of xenobiotics, i.e., levels of parent chemicals and/or metabolites, and thus their toxicity, CYP induction/inhibition data is needed for regulatory chemical toxicity hazard assessment. Utilizing available human in vivo pharmaceutical data, a successful validation was previ-ously conducted on the in vitro HepaRG™ CYP induction test method for measurement of induction of the three key human CYP enzymes CYP1A1/1A2, 2B6 and 3A4. However, further validation data was required to demonstrate applicability of the test method to also accurately detect CYP induction mediated by industrial and pesticidal chemicals. Here we report on a supplementary validation efforts to expand the chemical applicability domain beyond pharmaceutical chemicals for the HepaRG™ CYP induction test method. This was first carried out in two laboratories under the auspices of the EU Horizon2020-funded project GOLIATH. Laboratory trans-fer was demonstrated and reproducibility assessed for the original 10 selected proficiency pharmaceuticals plus three reference inducers together with six additional non-pharmaceutical ‘augmentation chemicals’. For the proficiency pharmaceuticals, the method transferred well to one laboratory and was reasonably transfera-ble for the second laboratory. For the augmentation chemicals proposed as additional proficiency chemicals, the test method achieved reasonable but not optimum reproducibility. Recommendations are proposed to im-prove the test method’s specificity regarding the uncertainty around borderline CYP inducing chemicals. Plain language summaryCytochrome P450 (CYP) enzymes help break down drugs and other chemicals in the body. Their activity can be increased or decreased by some chemicals, which can change how toxic the chemical is and when it is excreted. Because of this, CYP data is important for chemical safety assessments. A laboratory-based method using HepaRG™ cells was previously validated to measure how pharmaceutical chemicals change the activity of three key CYP enzymes. This study aimed to show that it also works well for industrial and pesticidal chemi-cals. In the EU-funded GOLIATH project, two laboratories tested 10 pharmaceutical and 6 non-pharmaceutical chemicals. The method showed good reliability and reproducibility for pharmaceuticals overall. For non-pharmaceutical chemicals, results were acceptable but less consistent. The study concludes that the method is useful for CYP induction testing, but improvements are needs to increase accuracy and better handle chem-icals that show weak or borderline CYP induction effects.
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BibTeX
@article{jacobs2026hepargtm,
title = {{HepaRGTM CYP induction test method augmentation part 1: The GOLIATH Study}},
author = {Miriam Jacobs and Elodie Person and Barbara Kubickova and Jorke Kamstra and Nicolas Cabaton and Sebastian Hoffmann and Agnès Jamin and Marlene Lacroix and Juliette Legler and Vesna Munic Kos and Sandra Nijmeijer and Theo Sinnige and Laurie Urien and Daniel Zalko},
journal = {ALTEX - Alternatives to Animal Experimentation},
year = {2026},
month = sep,
doi = {10.14573/altex.2606131},
url = {https://hal.science/hal-05783283v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - HepaRGTM CYP induction test method augmentation part 1: The GOLIATH Study
AU - Miriam Jacobs
AU - Elodie Person
AU - Barbara Kubickova
AU - Jorke Kamstra
AU - Nicolas Cabaton
AU - Sebastian Hoffmann
AU - Agnès Jamin
AU - Marlene Lacroix
AU - Juliette Legler
AU - Vesna Munic Kos
AU - Sandra Nijmeijer
AU - Theo Sinnige
AU - Laurie Urien
AU - Daniel Zalko
PY - 2026
DA - 2026/09/25
JO - ALTEX - Alternatives to Animal Experimentation
DO - 10.14573/altex.2606131
UR - https://hal.science/hal-05783283v1
AB - Cytochrome P450 (CYP) enzymes play a key role in the metabolism of both xenobiotics and endogenous com-pounds, and some CYP isoforms are susceptible to induction and/or inhibition by certain chemicals. As CYP induction/inhibition can significantly alter the in vivo fate of xenobiotics, i.e., levels of parent chemicals and/or metabolites, and thus their toxicity, CYP induction/inhibition data is needed for regulatory chemical toxicity hazard assessment. Utilizing available human in vivo pharmaceutical data, a successful validation was previ-ously conducted on the in vitro HepaRG™ CYP induction test method for measurement of induction of the three key human CYP enzymes CYP1A1/1A2, 2B6 and 3A4. However, further validation data was required to demonstrate applicability of the test method to also accurately detect CYP induction mediated by industrial and pesticidal chemicals. Here we report on a supplementary validation efforts to expand the chemical applicability domain beyond pharmaceutical chemicals for the HepaRG™ CYP induction test method. This was first carried out in two laboratories under the auspices of the EU Horizon2020-funded project GOLIATH. Laboratory trans-fer was demonstrated and reproducibility assessed for the original 10 selected proficiency pharmaceuticals plus three reference inducers together with six additional non-pharmaceutical ‘augmentation chemicals’. For the proficiency pharmaceuticals, the method transferred well to one laboratory and was reasonably transfera-ble for the second laboratory. For the augmentation chemicals proposed as additional proficiency chemicals, the test method achieved reasonable but not optimum reproducibility. Recommendations are proposed to im-prove the test method’s specificity regarding the uncertainty around borderline CYP inducing chemicals. Plain language summaryCytochrome P450 (CYP) enzymes help break down drugs and other chemicals in the body. Their activity can be increased or decreased by some chemicals, which can change how toxic the chemical is and when it is excreted. Because of this, CYP data is important for chemical safety assessments. A laboratory-based method using HepaRG™ cells was previously validated to measure how pharmaceutical chemicals change the activity of three key CYP enzymes. This study aimed to show that it also works well for industrial and pesticidal chemi-cals. In the EU-funded GOLIATH project, two laboratories tested 10 pharmaceutical and 6 non-pharmaceutical chemicals. The method showed good reliability and reproducibility for pharmaceuticals overall. For non-pharmaceutical chemicals, results were acceptable but less consistent. The study concludes that the method is useful for CYP induction testing, but improvements are needs to increase accuracy and better handle chem-icals that show weak or borderline CYP induction effects.
SN - 1868-596X
SN - 1868-8551
ER -