85 research outputs found
Thiopurine S-methyltransferase genetic polymorphism in the Tunisian population
Background: Determine the incidence of four thiopurine S-methyltransferase (TPMT) mutant alleles, TPMT*2, *3A, *3B and *3C in the Tunisian population involved in adverse drug reactions. Genomic DNAs were isolated from peripheral blood leucocytes of 119 healthy Tunisian volunteers. The frequencies of four allelic variants of the TPMT gene, TPMT*2, *3A, *3B, *3C were determined using allele specific polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism technique.Results: Of the 119 Tunisian subjects participating in this study, 117 subjects (98.3%) were homozygous for TPMT*1 and only two subjects (1.68%) were heterozygous for TPMT*1/*3A. The frequency of TPMT*3A mutant allele was 0.009.Conclusions: Our study provides the first data on the frequency of common TPMT variants in the Tunisian population. TPMT*3A, which causes the largest decrease in enzyme activity, seemed to be a unique variant allele found in this our population.Keywords: Thiopurine S-methyltransferase (TPMT); Pharmacogenetics; Tunisians; PC
Quantum mechanics/molecular mechanics modeling of drug metabolism:Mexiletine N-hydroxylation by cytochrome P450 1A2
The mechanism of cytochrome P450(CYP)-catalyzed
hydroxylation of
primary amines is currently unclear and is relevant to drug metabolism;
previous small model calculations have suggested two possible mechanisms:
direct N-oxidation and H-abstraction/rebound. We have modeled the
N-hydroxylation of (<i>R</i>)-mexiletine in CYP1A2 with
hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing
a more detailed and realistic model. Multiple reaction barriers have
been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct
N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers
indicate that the direct N-oxidation mechanism is preferred and proceeds
via the doublet spin state of Compound I. Molecular dynamics simulations
indicate that the presence of an ordered water molecule in the active
site assists in the binding of mexiletine in the active site, but
this is not a prerequisite for reaction via either mechanism. Several
active site residues play a role in the binding of mexiletine in the
active site, including Thr124 and Phe226. This work reveals key details
of the N-hydroxylation of mexiletine and further demonstrates that
mechanistic studies using QM/MM methods are useful for understanding
drug metabolism
Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis
CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls
Individual Preferences and Social Interactions Determine the Aggregation of Woodlice
n°e17389.info:eu-repo/semantics/publishe
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