The pharmacogenetics of carboxylesterases: <i>CES1</i> and <i>CES2</i> genetic variants and their clinical effect

Merali, Zahra; Ross, Stephanie; Paré, Guillaume

doi:10.1515/dmdi-2014-0009

Cited by 86 publications

(56 citation statements)

References 51 publications

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“…The coregulation mechanisms of CES gene expression is still unknown. However, both genes are located in close proximity to one another on chromosome 16 (CES1 on Ch16q12.2 and CES2 at Ch16q22.1) (Langmann et al, 1997;Merali et al, 2014), which might explain the coregulation of the expression of the two CES proteins. Knowledge about the coregulated expression of DMEs is important for PBPK modeling (Achour et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Cocaine (Pindel et al, 1997), heroin (Kamendulis et al, 1996), clopidogrel (Tang et al, 2006), aspirin (Tang et al, 2006), methylphenidate (Merali et al, 2014), enalapril/ramipril (Thomsen et al, 2014), oseltamivir , and irinotecan (Haaz et al, 1997) are some examples of drugs and prodrugs that undergo phase I metabolism by CESs, most of which are prescribed to children. In this study, hepatic CES1 and CES2 protein abundance in different pediatric age groups was determined and compared with the observed protein abundance in adults.…”

Section: Introductionmentioning

confidence: 99%

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Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants

et al. 2016

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The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and CES2 abundance (in picomoles per milligram total protein) increased approximately 5-fold (315.2 vs. 1664.4) and approximately 3-fold (59.8 vs. 174.1) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein abundance in pediatric and adult liver microsomes. The protein abundance data were then used to model in vivo PK of oseltamivir in infants using pediatric physiologically based PK modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric area under the curve, maximal plasma concentration, and time for maximal plasma concentration values were below 2.1-fold of the clinically observed values, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants

et al. 2016

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“…Six CES1 single-nucleotide polymorphisms have been identified that in vitro exhibit various degrees of decreased activity or increased promoter activity or in vivo are associated with altered drug disposition. Three CES2 single-nucleotide polymorphisms have been associated with decreased activity both in vitro and in vivo (reviewed in Merali et al, 2014). Whether any of these genetic variants function through altered protein levels versus changes in enzyme activity is unknown, however.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny

Hines

Simpson

McCarver

2016

Drug Metabolism and Disposition

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Human hepatic carboxylesterase 1 and 2 (CES1 and CES2) are important for the disposition of ester-and amide-bond-containing pharmaceuticals and environmental chemicals. CES1 and CES2 ontogeny has not been well characterized, causing difficulty in addressing concerns regarding juvenile sensitivity to adverse outcomes associated with exposure to certain substrates. To characterize postnatal human hepatic CES1 and CES2 expression, microsomal and cytosolic fractions were prepared using liver samples from subjects without liver disease (N = 165, aged 1 day to 18 years). Proteins were fractionated, detected, and quantitated by Western blotting. Median microsomal CES1 was lower among samples from subjects younger than 3 weeks (n = 36) compared with the rest of the population (n = 126; 6.27 vs. 17.5 pmol/mg microsomal protein, respectively; P < 0.001; Kruskal-Wallis test).Median cytosolic CES1 expression was lowest among samples from individuals between birth and 3 weeks of age (n = 36), markedly greater among those aged 3 weeks to 6 years (n = 90), and modestly greater still among those older than 6 years (n = 36; median values = 4.7, 15.8, and 16.6 pmol/mg cytosolic protein, respectively; P values < 0.001 and 0.05, respectively; KruskalWallis test). Median microsomal CES2 expression increased across the same three age groups with median values of 1.8, 2.9, and 4.2 pmol/mg microsomal protein, respectively (P < 0.001, both). For cytosolic CES2, only the youngest age group differed from the two older groups (P < 0.001; median values = 1.29, 1.93, 2.0, respectively). These data suggest that infants younger than 3 weeks of age would exhibit significantly lower CES1-and CES2-dependent metabolic clearance compared with older individuals.

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“…The transport pathway of irinotecan is shown in Figure 1. In addition to UGT1A1 polymorphism, polymorphisms of carboxylesterase ( CES ) and ATP-binding cassette ( ABC ) genes have been reported to affect the metabolism of irinotecan 8,9. In this review, the impact of UGT1A1 genotypes on irinotecan treatment will be discussed.…”

Section: Introductionmentioning

confidence: 99%

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

Takano¹,

Sugiyama²

2017

PGPM

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Mutations in the UGT1A1 gene have been implicated in Gilbert syndrome, which shows mild hyperbilirubinemia, and a more aggressive childhood subtype, Crigler–Najjar syndrome. To date, more than 100 variants have been found in the UGT1A1 gene. Among them, UGT1A1*28 and UGT1A1*6 have been reported to be associated with severe toxicities in patients treated with irinotecan-based chemotherapy by increasing the dose of SN-38 (7-ethyl-10-hydroxycamptothecin), an active form of irinotecan. Many association studies and meta-analyses have demonstrated the contribution of UGT1A1*28 and UGT1A1*6 polymorphisms to the toxicities caused by irinotecan-based therapy. The aim of this review was to evaluate the impact of these variants upon the toxicities and the efficacy of irinotecan-based chemotherapy.

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The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect

Cited by 86 publications

References 51 publications

Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants

Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants

Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

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