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

0090-9556/05/3312-1803-1810$20.00
DMD 33:1803-1810, 2005

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SIMULTANEOUS MEASUREMENT OF 23 ISOFORMS FROM THE HUMAN CYTOCHROME P450 FAMILIES 1 TO 3 BY QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION

Igor Girault, Nathalie Rougier, Christophe Chesné, Rosette Lidereau, Philippe Beaune, Ivan Bieche, and Isabelle de Waziers

Institut National de la Santé et de la Recherche Médicale (INSERM), E0017, Saint Cloud, France (R.L., I.B.); Centre René Huguenin, Saint-Cloud, France (R.L., I.B.); Société Biopredic International, Rennes, France. (I.G., N.R., C.C.); INSERM, U490, Paris, France (P.B., I.d.W.); and Université René Descartes, Paris, France (P.B., I.d.W.)

Drug metabolism in humans is essentially performed by three cytochrome P450 (P450) families (1 to 3), including 23 isoforms. The expression of these P450s is highly variable, and the rate and nature of the metabolites produced depend on the nature and the concentration of individual isoforms. P450 expression pattern is therefore a necessary tool to evaluate the effects of a given drug on P450 expression, its potential toxicity, and eventual interference 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 reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to evaluate the overall P450 expression pattern and measure human CYP1 to CYP3 mRNAs involved in drug metabolism. Our RT-PCR-based P450 mRNA assay enables us to quantify P450s 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 P450 expression in human primary hepatocytes. Since this method may be used to determine human P450 expression in any human tissue or cell culture, it is a valuable tool for reliable prediction of drug safety, drug toxicity, and drug-drug interference.

Address correspondence to: Isabelle de Waziers, INSERM UMR-S490, Laboratoire de Toxicologie Moléculaire, Faculté de Médecine, 45 rue des Saints Pères 75270 Paris Cedex 06, France. E-mail: isabelle.waziers{at}univ-paris5.fr




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