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1. Int J Alzheimers Dis. 2012;2012:518901. Epub 2012 Mar 14.

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics.

Cacabelos R, Martínez R, Fernández-Novoa L, Carril JC, Lombardi V, Carrera I,
Corzo L, Tellado I, Leszek J, McKay A, Takeda M.

EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic
Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela
University, 15165 Bergondo, Spain.

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.

PMID: 22482072 [PubMed - in process]