The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction.

Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene affecting enzyme activity are involved in interindividual variability in drug efficiency/toxicity. Four phenotypic groups are found in the general population: ultra rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. The AmpliChip CYP450 test is the first genotyping array allowing simultaneous analysis of 33 CYP2D6 alleles. The main aim of this study was to evaluate the performance of this test in CYP2D6 phenotype prediction. We first verified the AmpliChip CYP450 test genotyping accuracy for five CYP2D6 alleles routinely analysed in our laboratory (alleles 3,4,5,6, x N; n=100). Results confirmed those obtained by real-time PCR. Major improvements using the array are the detection of CYP2D6 intermediate alleles and identification of the duplicated alleles. CYP2D6 phenotype was determined by assessing urinary elimination of dextromethorphan and its metabolite dextrorphan and compared to the array prediction (n=165). Although a low sensitivity of UM prediction by genotyping was observed, phenotype prediction was optimal for PM and satisfying for EM and IM.

Protein structure computing in the genomic era.

Functional analysis of the proteins discovered in fully sequenced genomes represents the next major challenge of life science research. Computational methods play a crucial role in this activity and, among them, comparative protein modelling is of great assistance during the rational design of mutagenesis experiments. Our aim over the last several years has been to further the use of 3-D model structures in this field. Therefore, we have developed a comparative protein modelling environment composed of the Swiss-PdbViewer (sequence to structure workbench and viewing program), SWISS-MODEL (internet-based server for model generation) and a database of a model generated with 3DCrunch.