|Keywords:||Human Carboxylesterase 1; Biomarkers; Cytochrome P450; Probes|
|Full text PDF:||http://rudar.ruc.dk/handle/1800/21539|
Personalized medicine is an evolving medical field aiming to customize treatments through genetic profiling, resulting in an improved therapeutic response and minimizing adverse effects. Pharmacokinetics refers to the body’s response to xenobiotics. Different responses can be due to variations in the genes coding for drug-metabolizing enzymes. Hence, absent, increased or decreased enzyme expression can be caused by gene polymorphisms or copy number variants. To study the altered efficiency of hCES1 metabolism due to pharmacokinetic changes, it is essential to look at the cytochrome P450 (CYP) enzymes. In drug metabolism, six CYP enzymes, including CYP2D6 (2D6) and CYP3A4 (3A4), play an imperative role and account for most of the metabolism of widely prescribed drugs metabolized in the liver. In this study, 2D6 and 3A4 are used as models for human carboxylesterase 1 (hCES1) to explain how the properties of hCES1 can be used to benefit the personalization of medicine. hCES1 metabolizes both endogenous and xenobiotic compounds. It is expressed in various tissues though mostly in the liver. The CES1 gene expression seems to be surprisingly constant between individuals in the human population though the enzymatic hCES1 activity differs significantly. This can be due to hCES1 SNPs that are identified and classified as possibly damaging to protein structure and function or due to mutations in the hCES1 gene resulting in a considerably decreased catalytic function of the hCES1 enzyme. hCES1 activity is regulated at genome and enzyme level, exhibiting behavior from both CYP models. There are not yet any probes or biomarkers applicable for clinical use, since the one hCES1 probe that is found, is only tested in hepatic cells. More research is needed, in order to find a probe or biomarker that is more accessible. Another approach could be to apply metabolomics, to determine the metabotype of a patient.