Functional Gene Variants of CYP3A4 Werk, A N; Cascorbi, I
Clinical pharmacology and therapeutics,
September 2014, Letnik:
96, Številka:
3
Journal Article
Recenzirano
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more drugs in clinical use than any other foreign compound–metabolizing enzyme in humans. Recently, increasing evidence has been found ...showing that variants in the CYP3A4 gene have functional significance and—in rare cases—lead to loss of activity, implying tremendous consequences for patients. This review article highlights the functional consequences of all CYP3A4 variants recognized by the Human Cytochrome P450 (CYP) Allele Nomenclature Database.
Clinical Pharmacology & Therapeutics (2014); 96 3, 340–348. advance online publication 16 July 2014. doi:10.1038/clpt.2014.129
Objectives At the conclusion of this lecture, the participant will be able to distinguish mechanisms of chemoresistances towards tyrosine kinase inhibitors (TKI) such as somatic mutations of the ...target gene or modulation of efflux transporters through pharmacogenetic, microRNA and DNA-methylation in particular of imatinib in treatment of CML. ...pharmacokinetically mediated...
Interindividual differences in the pharmacokinetics of a number of drugs are often due to hereditary polymorphisms of drug‐metabolizing enzymes. Most important is cytochrome P4502D6 (CYP2D6), also ...known as debrisoquine/sparteine hydroxylase. It catalyzes hydroxylation or demethylation of more than 20% of drugs metabolized in the human liver, such as neuroleptics, antidepressants, some β‐blockers and many others like codeine. About 7%−10% of Caucasians lack any CYP2D6 activity due to deletions and frame‐shift or splice‐site mutations of the gene. About 1%−3% of Middle‐Europeans, but up to 29% of Ethiopians display gene duplications, leading to elevated so‐called ultrarapid metabolization rates. Meanwhile there is now a much better understanding of the genetic background of poor, intermediate, extensive and ultrarapid metabolizers, enabling a more precise DNA genotyping‐based prediction of plasma levels. Since there is evidence that deteriorated drug elimination partly accounts for drug side‐effects, CYP2D6 genotyping could contribute to an individualized and therefore optimized drug therapy.
The pharmacological treatment of chronic pain is generally hampered by a limited clinical outcome. Hence, there is a strong need for new therapeutic concepts considering the identification of novel ...targets and related drugs, but also optimization of established therapeutic regimes through individualization. In this issue, focused on “Pain,” we discuss some of the recent new concepts in pain treatment, understanding of pain heterogeneity, and subsequent optimization of analgesic treatment, but also novel insights into interactions of nonopioids.
Epigenetics in Drug Response Cascorbi, I; Schwab, M
Clinical pharmacology and therapeutics,
05/2016, Letnik:
99, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Hereditary genetic variation has been identified to contribute significantly to drug response. More recently, there is increasing evidence that individual phenotypic differences may also result from ...epigenetic alterations such as histone‐acetylation or DNA‐methylation. Moreover, interactions with noncoding RNAs contribute to protein expression and may modulate drug action. Currently, intriguing developments of novel therapeutic approaches through epigenetic drugs are emerging. The overall complexity of epigenetics in drug action, however, is so far only little understood.
Inter-individual drug effects are subject to substantial variability. There are multiple reasons based on pathophysiological factors and environmental interactions, but also genetic characteristics. ...Groundbreaking successes have been achieved in the field of pharmacogenomics and toxicogenomics. In particular, the identification of hereditary polymorphisms in genes of the cytochrome P450 system and phase II-enzymes such as TMPT contributed considerably to the explanation of the individually varying pharmacokinetics of a number of drugs. Furthermore, hereditary variations in genes of membrane drug transporters were recently discovered. Along with these factors, which could influence pharmacokinetics, strong efforts have been undertaken to clarify the role of genetic polymorphisms in receptors or signal transduction proteins modulating drug efficacy. Particularly for malignant diseases such as bladder or lung cancer, polymorphic foreign compound metabolizing enzymes have been identified as susceptibility factors, modulating an individual's cancer risk dependent on the extent of environmental exposure.
This review focuses on the role of the polymorphic phase I enzymes cytochrome P450 1A1, 1A2, 1B1, 2C9, 2C19, 2D6, 3A5 and myeloperoxidase as well as on the phase II-enzymes arylamine
N-acetyltransferases 1 and 2, glutathione
S-transferases M1 and T1, and thiopurine
S-methyltranferases as detoxifying but also toxifying factors, modulating pharmacokinetics and disease susceptibility.
Interindividual differences in expression of ADME genes are controlled by both genetic and epigenetic factors. Much emphasis has been made to describe the genetic influence, whereas the epigenetic ...part is not fully understood. Currently, we utilize mainly genetic biomarkers for optimization of drug therapy, although many rare genetic variants are not taken into consideration. Now, also epigenomic biomarkers are at hand and together genetic and epigenetic biomarkers can indeed improve the predictability of drug treatment.
Genetic information is increasingly used to optimize clinical treatment of patients, but obstacles remain to practical implementation as well as challenges to our understanding of genetic variation ...in drug response. These areas that particularly require research attention include gene–environment interactions, the consequences of genetic variation, and the impact of epigenetics on gene expression and function. In this issue of Clinical Pharmacology & Therapeutics focused on pharmacogenetics, we discuss some of the recent advances in understanding from a variety of viewpoints.
Clinical Pharmacology & Therapeutics (2014); 95 3, 231–235. doi:10.1038/clpt.2013.235
To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the ...MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
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