Publications by authors named "Yadira X Perez-Paramo"

5 Publications

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Pharmacogenetics factors influencing smoking cessation success; the importance of nicotine metabolism.

Expert Opin Drug Metab Toxicol 2021 Mar 29;17(3):333-349. Epub 2020 Dec 29.

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA.

: Smoking remains a worldwide epidemic, and despite an increase in public acceptance of the harms of tobacco use, it remains the leading cause of preventable death. It is estimated that up to 70% of all smokers express a desire to quit, but only 3-5% of them are successful.: The goal of this review was to evaluate the current status of smoking cessation treatments and the feasibility of implementing personalized-medicine approaches to these pharmacotherapies. We evaluated the genetics associated with higher levels of nicotine addiction and follow with an analysis of the genetic variants that affect the nicotine metabolic ratio (NMR) and the FDA approved treatments for smoking cessation. We also highlighted the gaps in the process of translating current laboratory understanding into clinical practice, and the benefits of personalized treatment approaches for a successful smoking cessation strategy.: Evidence supports the use of tailored therapies to ensure that the most efficient treatments are utilized in an individual's smoking cessation efforts. An understanding of the genetic effects on the efficacy of individualized smoking cessation pharmacotherapies is key to smoking cessation, ideally utilizing a polygenetic risk score that considers all genetic variation.
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March 2021

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Pharmacogenomics J 2020 08 21;20(4):586-594. Epub 2020 Jan 21.

Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico.

Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3'-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.
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August 2020

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico.

Arch Cardiol Mex 2019 ;89(4):324-329

Department of Genetics, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, Mexico.

Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity.

Materials And Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction.

Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients.

Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).
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September 2020

Nicotine-'-Oxidation by Flavin Monooxygenase Enzymes.

Cancer Epidemiol Biomarkers Prev 2019 02 31;28(2):311-320. Epub 2018 Oct 31.

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.

Background: The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine-'-oxide (NOX) formation.

Methods: Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type s 1-5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine.

Results: A strong inverse correlation was observed between the ratio of urinary 3'-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone ( = -0.383; < 0.001) or NOX measured as a ratio of total nicotine metabolites ( = -0.414; < 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2 isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine ( > 5.0 mmol/L). Significant ( < 0.05) decreases in '-oxidation activity ( / ) were observed for the FMO1, FMO3, FMO3, FMO3, and FMO3 variants when compared with their respective wild-type isoforms; the truncated FMO2 isoform exhibited no enzyme activity.

Conclusions: These data indicate that increases in nicotine-'-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine-'-oxidation.

Impact: Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects.
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February 2019

CYP2D6 in Amerindians from Southern Mexico: low variability and higher frequency of functional alleles.

Drug Metab Pers Ther 2015 Dec;30(4):231-8

Background: Several functional and nonfunctional CYP2D6 variants have been associated with interindividual and interethnic variability in pharmacological responses. The aim of this article was to study the diversity and the interpopulation relationships of CYP2D6 variants of south Native Mexicans to define predicted phenotypes.

Contents: A fully systematic review of CYP2D6 variants reported in Amerindian populations before 2015 was performed (NCBI, Google Scholar, and 1000 Genomes Project databases). Allele data were analyzed by methods such as heat map, dissimilarity matrix, dendogram, and principal component analysis using complete-linkage clustering method. Five original studies on CYP2D6 covering 13 Native Mexican populations were identified; three of these described CYP2D6 allele frequencies were in south Native Mexican populations. Overall, CYP2D6 allele variability is scarce in southern Native Mexican populations: besides the functional alleles *1 and *2 and the null variant *4, the other variants have frequencies <0.05. This implies that most of the southern Native Mexican populations may be considered CYP2D6 extended metabolizers. The statistical analyses tend to cluster the native communities by their geographical origin, but in a disperse pattern suggesting distinct subpopulation structures.

Conclusions: CYP2D6 functional variants are prevalent in Native Mexicans, and they may be predicted as extended drug metabolizers. In addition, allele frequencies are related to the geographic distribution of the Amerindian groups and display important population stratification.
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December 2015