Construction of Several Human-derived Stable Cell Lines Displaying Distinct Profiles of CYP3A4 Induction

doi:10.2133/dmpk.21.99

Drug Metabolism and Pharmacokinetics

Volume 21, Issue 2, 2006, Pages 99-108

https://doi.org/10.2133/dmpk.21.99 Get rights and content

Summary:

Cell lines which stably express reporter proteins through CYP3A4 gene activation have been developed for use in predicting CYP3A4 induction. Twelve clones showing distinct profiles on chemicalinduced response were isolated. Among them, two clones showing high response for CYP3A4 inducers, namely clone 3-1-10 and 3-1-20, were further evaluated for their sensitivities, reproducibilities and applicabilities to predict CYP3A4 induction in human. Clone 3-1-10 showed higher response to rifampicin than to clotrimazole, whereas clone 3-1-20 had rather higher response to clotrimazole. Optimal plating density and highly reproducible response were observed at the range of 1.65–5.0 × 10⁴ cell Wcm². Clear induction responses of more than ten chemicals were observed in both cell lines. The reporter activity was further dramatically increased after an introduction of human PXR. Induction with rifampicin was, however, not much altered between the absence and presence of hPXR. The luciferase activity remained unaltered and showed little fluctuation during the culture for more than 6 months.

Due to the strikingly high sensitivity and reproducibility of this system, as compared to previously published systems, these HepG2-derived cell lines showing distinct response profiles as developed in the present study will offer high advantages for chemical screening of CYP3A4 inducibility.

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Regular ArticleConstruction of Several Human-derived Stable Cell Lines Displaying Distinct Profiles of CYP3A4 Induction

Summary:

Lancet

Trends Pharmacol. Sci.

Chem. Biol. Interact.

Biochem. Pharmacol.

Eur. J. Pharm. Sci.

Cell

Drug Metab. Pharmacokinet.