PHARMACOGENETIC VARIATION AT CYP2D6, CYP2C9, AND CYP2C19: Population Genetic and Forensic Aspects

.......................................................................................................................8 REVIEW OF THE LITERATURE...................................................................................10 1 Pharmacogenetics ...........................................................................................................10 2 Drug-Metabolizing Enzymes..........................................................................................11 3 CYP Enzymes.................................................................................................................12 3.1 General Characteristics ...........................................................................................12 3.2 CYP2D6..................................................................................................................14 3.3 CYP2C9..................................................................................................................18 3.4 CYP2C19................................................................................................................20 4 Genetic Variation at CYP2D6, CYP2C9, and CYP2C19 in Human Populations...........22 5 Factors Affecting the Genetic Diversity at CYP Genes..................................................22 5.1 Evolution of the Gene Superfamily ........................................................................22 5.2 Neutral Evolution in Human Populations...............................................................23 5.3 Selective Pressures..................................................................................................24 6 Clinical Pharmacogenetics .............................................................................................25 6.1 From Genotypes to Phenotypes ..............................................................................25 6.2 Clinical Applications Involving CYP2D6, CYP2C9, and CYP2C19 ....................28 6.2.1 Cancer Treatment ...........................................................................................28 6.2.2 Oral Anticoagulation Therapy........................................................................28 6.2.3 Proton Pump Inhibitor Therapy .....................................................................29 6.2.4 Psychiatric Drug Therapy ..............................................................................30 7 Postmortem Pharmacogenetics.......................................................................................33 AIMS OF THE STUDY....................................................................................................35 MATERIALS AND METHODS ......................................................................................36 1 Samples...........................................................................................................................36 1.1 Population Genetic Studies (II, III).........................................................................36 1.2 Postmortem Cases (IV, V) ......................................................................................36 2 Genotyping .....................................................................................................................37 2.1 DNA Extraction (III-V) ..........................................................................................37