Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics

Ab initio crystal structure determination of two chain functionalized pyrroles from synchrotron X-ray powder diffraction data

The crystal structure of two chain functionalized pyrroles, methyl 1-benzyl-5-(1-(4-chlorobenzoyloxy)-2-methoxy-2-oxoethyl)-4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate and methyl 1-benzy1-4-(biphenyl-4-yl)-5-(1-(4-biphenylcarbonyloxy)-2-methoxy-2-oxoethyl)-1H-pyrrole-2-carboxylate, which are both important active candidates as antitumoral agents, have been obtained ab initio from synchrotron X-ray powder diffraction data. Both compounds crystallize in the monoclinic system (space group P2(1)/c), with a = 20.2544(3) angstrom, b = 6.80442(9) angstrom, c = 21.1981(3) angstrom, beta = 111.6388(9)degrees and a = 29.7747(6) angstrom, b = 6.27495(14) angstrom, c= 18.8525(3) angstrom, beta = 107.053(2)degrees, respectively. These structures were determined using a direct space approach, by means of Monte Carlo technique, followed by Rietveld refinement.The financial support from the Spanish Ministerio de Ciencia e Innovación (PI201060E013) is also acknowledged.Peer Reviewe

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia