Construction of several human-derived stable cell lines displaying distinct profiles of CYP3A4 induction.

Wachiraporn Noracharttiyapot, Yoko Nagai, Tsutomu Matsubara, Masaaki Miyata, Miki Shimada, Kiyoshi Nagata, Yasushi Yamazoe

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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 chemical-induced 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 x 10(4) cell/cm2. 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.

Original languageEnglish
Pages (from-to)99-108
Number of pages10
JournalDrug metabolism and pharmacokinetics
Volume21
Issue number2
DOIs
Publication statusPublished - 2006 Apr
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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