QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.009423v1 35/2/215    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meneses-Lorente, G. Articles by Sohal, B. Search for Related Content PubMed PubMed Citation Articles by Meneses-Lorente, G. Articles by Sohal, B.

Utility of Long-Term Cultured Human Hepatocytes as an in Vitro Model for Cytochrome P450 Induction

Department of Medicinal Chemistry (Drug Metabolism Section), Merck Sharp and Dohme Research Laboratories, Harlow, Essex, United Kingdom (G.M.-L., C.P., R.H., A.P.W., B.S.); and Biopredic International, Rennes, France (C.G., C.C.)

Cytochrome P450 (P450) induction may have considerable implications for drug therapy. Therefore, understanding the induction potential of a new chemical entity at an early stage in discovery is crucial to reduce the risk of failure in the clinic and help the identification of noninducing chemical structures. Availability of human viable tissue often limits evaluation of induction potential in human hepatocytes. A solution is to increase the time period during which the hepatocytes remain viable. In this study we have investigated the induction of several P450 isozymes in long-term cultured hepatocytes compared with short-term cultured hepatocytes from the same individuals. Short- and long-term cultured primary hepatocytes isolated from each individual were cultured in a 96-well format and treated for 24 h with a range of prototypical P450 inducers and Merck Research Laboratories compounds. CYP3A4, 1A1, 1A2, 2B6, and 2C9 mRNA levels were measured using quantitative real-time reverse transcriptase-polymerase chain reaction (TaqMan) from the same cultured hepatocyte wells. CYP3A4, 1A1, 1A2, 2B6, and 2C9 were shown to be inducible in long-term cultured hepatocytes. The -fold induction varied between donors, and between short- and long-term cultured hepatocytes from the same donor. However, this variability can be controlled by normalizing data from each hepatocyte preparation to a positive control. The use of long-term cultured hepatocytes on 96-well plates has proven to be sensitive, robust, and convenient for assessing P450 induction potential of new compound entities during the drug discovery process.

This article has been cited by other articles:

				L. Svecova, R. Vrzal, L. Burysek, E. Anzenbacherova, L. Cerveny, J. Grim, F. Trejtnar, J. Kunes, M. Pour, F. Staud, et al. Azole Antimycotics Differentially Affect Rifampicin-Induced Pregnane X Receptor-Mediated CYP3A4 Gene Expression Drug Metab. Dispos., February 1, 2008; 36(2): 339 - 348. [Abstract] [Full Text] [PDF]

				V. Dixit, N. Hariparsad, F. Li, P. Desai, K. E. Thummel, and J. D. Unadkat Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions Drug Metab. Dispos., October 1, 2007; 35(10): 1853 - 1859. [Abstract] [Full Text] [PDF]