Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

Yamada, So; Richardson, Kathryn; Tang, Mila; Halaschek-Wiener, Julius; Cook, Victoria; FitzGerald, J. Mark; Elwood, Kevin; Marra, Fawziah; Brooks‐Wilson, Angela

doi:10.1038/tpj.2010.5

Cited by 49 publications

(35 citation statements)

References 41 publications

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“…[2,9] In addition, -75T>G polymorphism was associated with the reduced appetite in attention deficit-hyperactivity disorder (ADHD) youths treated with methylphenidate [10] and the isoniazid-induced hepatotoxicity in latent tuberculosis infection patients. [11] Taken together, these findings suggest that CES1 gene variants can lead to clinically significant alterations in…”

Section: Introductionmentioning

confidence: 87%

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

Jung

Jeong

Shin

et al. 2014

Transl Clin Pharmacol

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Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyzes various exogenous compounds. Single nucleotide polymorphisms (SNPs) of CES1 may lead to inter-individual metabolic variability of its substrates. The allele and haplotype frequencies of known SNPs have been demonstrated to vary among ethnic groups. We analyzed genetic variations of CES1 in a Korean population. Direct sequencing of all exons and flanking regions of the CES1 gene was performed on samples obtained from 200 Koreans. We identified 41 SNPs. The most frequent SNPs was -914G>C (frequency: 99.5%), followed by 4256G>A (frequency: 65.8%), -75T>G (frequency: 59.3%). Haplotype analysis using the identified SNPs revealed fifteen haplotypes (≥1% haplotype frequency) in our samples. The most frequent haplotype was Hap1 (frequency: 15.4%). Among the identified 41 SNPs, nine of which are novel variants and 14 SNPs were nonsynonymous variants. Using the functional predictive software PolyPhen-2, the G19V, E221G, and A270S variants were predicted to be most likely damaging to the function and structure of CES1. In-vitro analyses for two of these variants have been previously performed; however, functional evaluation of E221G (11657A>G, rs200707504) still needs to be conducted. Therefore, further studies are warranted to characterize the functional impact of E221G on CES1 activity.

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Section: Introductionmentioning

confidence: 87%

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

Jung

Jeong

Shin

et al. 2014

Transl Clin Pharmacol

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“…Beyond the nonsynonymous SNPs, a number of SNPs within the promoter and 59-untranslated region (59-UTR) of CES1A1 and CES1A2/CES1A3 genes have been reported (Geshi et al, 2005;Yoshimura et al, 2008;Sai et al, 2010;Yamada et al, 2010). Among them, -816A.C was reported to be significantly associated with the efficacy of the angiotensin-converting enzyme inhibitor prodrug imidapril (Geshi et al, 2005).…”

Section: Tablementioning

confidence: 99%

Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

Zhu

Wang

Gawronski

et al. 2012

J Pharmacol Exp Ther

168

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Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxoclopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice.

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“…As these variants have low allele frequencies (o5%) in all ethnic groups so far investigated, 11 their usefulness for pharmacogenetics studies is small. Recently, Yamada et al 13 resequenced the CES1 gene bidirectionally in 170 subjects, detecting genetic variants that were evaluated in relation to their potential usefulness in pharmacogenomic studies. Among the polymorphisms described, one, À75 T4G (rs3815583), located in the 5 0 -untranslated region presented a trend for association with hepatotoxicity determined by isoniazid use.…”

Section: Introductionmentioning

confidence: 99%

Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate

et al. 2012

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Carboxylesterase 1 is the enzyme involved in methylphenidate (MPH) metabolism. The aim of this study was to evaluate the association between a À75 T4G polymorphism and appetite reduction in children with attention-deficit/hyperactivity disorder (ADHD). A sample of 213 children with ADHD was investigated. The primary outcome was appetite reduction measured by the Barkley Stimulant Side Effect Rating Scale applied at baseline, at 1 and 3 months of treatment. MPH doses were augmented until no further clinical improvement or significant adverse events occurred. The G allele presented a trend for association with appetite reduction scores (P ¼ 0.05). A significant interaction between the G allele and treatment over time for appetite reduction scores was also observed (P ¼ 0.03). The G allele carriers presented a higher risk for appetite reduction worsening when compared with T allele homozygotes (odds ratio ¼ 3.47, P ¼ 0.01). The present results suggest an influence of carboxylesterase 1 À75 T4G polymorphism on the worsening of appetite reduction with MPH treatment in youths with ADHD.The Pharmacogenomics Journal (2013) 13, 476--480; doi:10.1038/tpj.2012.25; published online 12 June 2012Keywords: adverse reaction; appetite reduction; attention deficit hyperactivity disorder; carboxylesterase 1; methylphenidate; pharmacogenetics INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child and adolescent psychiatric disorders, affecting around 5% of children worldwide.1 Stimulants like methylphenidate (MPH) and amphetamine are widely recognized as the first-line treatment for ADHD, and they have been prescribed for more than 60 years.2 The use of MPH in children and adolescents with ADHD is associated to rates of effectiveness around 70% and the medication is generally well tolerated.3 One of the most recognized brain effect of MPH and its potential mechanism of action for improvement of ADHD symptoms is dopamine transporter blockade, although MPH blocks efficiently norepinephrine transporter as well.

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Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

Cited by 49 publications

References 41 publications

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate

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