Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.
Basic Clin Pharmacol Toxicol
; 122(3): 341-345, 2018 Mar.
Article
em En
| MEDLINE
| ID: mdl-28990360
ABSTRACT
Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10-13 ) and 31% (p = 2.5 × 10-8 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ticlopidina
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Inibidores da Agregação Plaquetária
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Hidrolases de Éster Carboxílico
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Regulação Enzimológica da Expressão Gênica
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Agregação Plaquetária
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Polimorfismo de Nucleotídeo Único
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Variantes Farmacogenômicos
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
País como assunto:
Europa
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article