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Drug Metabolism and Disposition Fast Forward
First published on August 31, 2005; DOI: 10.1124/dmd.105.005173

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Received for publication April 14, 2005.
Revised August 14, 2005.
Accepted for publication August 15, 2005.

Simultaneous measurement of 23 isoforms from the human cytochrome P450 families 1-3 by quantitative RT-PCR

Igor Girault 1, Nathalie Rougier 2, Christophe Chesne 2, Rosette Lidereau 1, Philippe Beaune 3, Ivan Bieche 1, Isabelle de Waziers 3*

1 INSERM E0017 2 Biopredic International 3 INSERM U490

* Address correspondence to: E-mail: isabelle.waziers{at}univ-paris5.fr

Abstract

Drug metabolism in humans is essentiall performed by three CYP families (1 to 3), including 23 isoforms. The expression of these CYPs is highly variable and the rate and nature of the metabolites produced depend on the nature and the concentration of individual isoforms. CYP expression pattern is therefore a necessary tool to evaluate the effects of a given drug on CYP expression, its potential toxicity and eventual interferences with other drugs administered concomitantly. This pattern provides a general outline of the induction/repression effects of drugs leading to further mechanistic studies. A real-time quantitative RT-PCR assay was developed to evaluate overall CYP expression pattern and measure human CYP1 to CYP3 mRNAs involved in drug metabolism. Our RT-PCR-based CYP mRNA assay enables us to quantify CYPs rapidly with high specificity, a single annealing temperature and low amounts of biological sample. All 23 single assays were validated by assessing the effects (induction or repression) of known inducers (ethanol, 3-methylcholanthrene, rifampicin, dexamethasone, phenobarbital) on CYP expression in human primary hepatocytes. As this method may be used to determine human CYP expression in any human tissue or cell culture, it is a valuable tool for reliable prediction of drug safety, drug toxicity and drug-drug interferences.


Key words: CYP expression, CYP induction, CYP inhibition, cytochrome P450 isoforms, drug toxicity, drug-drug interactions, hepatocytes, human CYP enzymes


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