Редактирование: CES1 (раздел)

==Publications==

{{medline-entry
|title=[Comparative Study of Hydrolase Activity in Skin with Liver and Intestine, and Its Aging Relation of Carboxylesterase Expression in Cynomolgus Monkey and Beagle Dog].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31061351
|abstract=The hydrolysis activity and expression level of carboxylesterase (CES) in skin were compared with liver and intestine in the same individual of beagle dog and cynomolgus monkey, and their aging effects were studied. [[CES1]] isozymes were mainly present in skin of both animals. The dermal hydrolysis activity was about 10 and 40% of hepatic activity in beagle dog and cynomolgus monkey, respectively. In beagle dog, the hydrolysis activity and the expression level of CES isozyme in liver and skin were nearly the same between 2- and 11-year-old individuals. On the other hand, the dermal hydrolase activity was lower in young individual than in old, in contrast to slight increase of hepatic and intestinal activity in old cynomolgus monkey. These differences by aging in cynomolgus monkey were related to the expression of [[CES1]] proteins and their mRNA. Furthermore, mRNA level of human CES was investigated using total RNA of two individuals (63 and 85 years old). The two individuals showed approximately 2-fold higher expression of hCE2 than hCE1 in human skin.
|mesh-terms=* Aged, 80 and over
* Aging
* Animals
* Carboxylic Ester Hydrolases
* Dogs
* Female
* Gene Expression
* Humans
* Hydrolases
* Hydrolysis
* Intestines
* Isoenzymes
* Liver
* Macaca fascicularis
* Male
* Middle Aged
* RNA, Messenger
* Skin
|keywords=* aging effect
* carboxylesterase
* hydrolysis activity
* mRNA level
* skin
|full-text-url=https://sci-hub.do/10.1248/yakushi.18-00228
}}
{{medline-entry
|title=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.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27895113
|abstract=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.
|mesh-terms=* Adult
* Aging
* Carboxylesterase
* Carboxylic Ester Hydrolases
* Chromatography, Liquid
* Cytosol
* Humans
* In Vitro Techniques
* Infant
* Liver
* Microsomes, Liver
* Models, Biological
* Oseltamivir
* Proteomics
* Tandem Mass Spectrometry

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267516
}}
{{medline-entry
|title=Identifying clinically relevant sources of variability: The clopidogrel challenge.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27557470
|abstract=High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. [[CYP2C19]] polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy. When considering the combined impact of these covariates, our analysis results indicate that higher maintenance doses are required for [[CYP2C19]] intermediate metabolizers and poor metabolizers compared to extensive metabolizers and that respective maintenance doses have to be further increased for obese subjects for each of these [[CYP2C19]] phenotypes. In addition, interindividual differences in the fraction absorbed and the [[CES1]] activity were identified as sources of interindividual differences in clopidogrel's active metabolite concentrations and, thus, platelet reactivity.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Body Mass Index
* Clopidogrel
* Computer Simulation
* Cytochrome P-450 CYP2C19
* Cytochrome P-450 Enzyme System
* Diabetes Mellitus
* Dose-Response Relationship, Drug
* Drug Interactions
* Female
* Gastrointestinal Absorption
* Half-Life
* Humans
* Liver
* Male
* Metabolic Clearance Rate
* Middle Aged
* Models, Biological
* Obesity
* Platelet Aggregation
* Platelet Aggregation Inhibitors
* Polymorphism, Genetic
* Socioeconomic Factors
* Ticlopidine

|full-text-url=https://sci-hub.do/10.1002/cpt.459
}}
{{medline-entry
|title=Age-Dependent Human Hepatic Carboxylesterase 1 ([[CES1]]) and Carboxylesterase 2 ([[CES2]]) Postnatal Ontogeny.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26825642
|abstract=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; Kruskal-Wallis 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.
|mesh-terms=* Adolescent
* Age Factors
* Aging
* Carboxylesterase
* Carboxylic Ester Hydrolases
* Child
* Child, Preschool
* Cytosol
* Female
* Humans
* Infant
* Infant, Newborn
* Liver
* Male
* Microsomes, Liver

|full-text-url=https://sci-hub.do/10.1124/dmd.115.068957
}}
{{medline-entry
|title=Distinct patterns of aging effects on the expression and activity of carboxylesterases in rat liver and intestine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24271336
|abstract=The age-associated alteration in expression levels of carboxylesterases (CESs) can affect both intestinal and hepatic first-pass metabolism after oral administration of xenobiotic esters such as prodrugs. In this study, the age-related expression of CES isozymes and hydrolase activities were simultaneously investigated in liver, jejunum, and ileum from 8-, 46-, and 90-week-old rats. Rat liver expresses three major [[CES1]] isozymes, Hydrolase A, Hydrolase B, and Hydrolase C, as well as one minor [[CES1]] (Egasyn) and three minor [[CES2]] isozymes (RL4, AY034877, and D50580). The mRNA and protein levels of major hepatic [[CES1]] isozymes were decreased in an age-dependent manner, while those of minor CESs were maintained in all age groups. The hepatic hydrolase activity for temocapril was decreased in an age-dependent manner, accompanied by downregulation of Hydrolase B/C mRNA, while age-independent hydrolysis of propranolol derivatives was observed in rat liver, due to the contribution of Egasyn. Rat small intestine expresses one major [[CES2]] (RL4) and four minor CESs (Hydrolase B, Hydrolase C, Egasyn, and AY034877). Interestingly, the expression of RL4 was age-dependently increased in both jejunum and ileum, while minor isozymes showed a constant expression across a wide age range. The up-regulation of RL4 expression with aging led to an increase of intestinal hydrolase activities for temocapril and propranolol derivatives. Consequently, age-dependent changes in the expression of CES isozymes affect the hydrolysis of xenobiotics in both rat liver and small intestine. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Biotransformation
* Carboxylic Ester Hydrolases
* Gene Expression Regulation, Enzymologic
* Ileum
* Isoenzymes
* Jejunum
* Liver
* Male
* RNA, Messenger
* Rats
* Rats, Wistar
* Substrate Specificity

|full-text-url=https://sci-hub.do/10.1124/dmd.113.054551
}}
{{medline-entry
|title=Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19487248
|abstract=Carboxylesterase (CES) 1 and [[CES2]] are two major hepatic hydrolases responsible for the metabolism of numerous endogenous and exogenous compounds. In this study, age- and sex-dependent expression and activity of [[CES1]] and [[CES2]] were investigated using both animal models and individual human liver s9 samples. The expression and activity of mouse [[CES1]] (m[[CES1]]) and m[[CES2]] in the liver were markedly lower in newborns relative to adults and increased gradually with age, approximating levels of adult animals by age 2 to 4 weeks. Likewise, the average human [[CES1]] (h[[CES1]]) expression in the subjects <1 year of age was significantly lower than that of pooled samples. In particular, h[[CES1]] expression in the 13-day and 1-month-old subjects was just 20.3 and 11.1%, respectively, of the pooled sample values. In addition, the subjects <1 year of age exhibited a trend suggestive of low h[[CES2]] expression, but this difference failed to reach statistical significance because of large interindividual variability. The expression and activity of m[[CES1]] and m[[CES2]] were not significantly altered after the animals were treated with human growth hormone, indicating growth hormone may not be associated with the low level of CES expression during early developmental stages. No significant differences of the expression and activity of m[[CES1]] and m[[CES2]] were observed between sexually mature male and female mice. In conclusion, the expression and activity of [[CES1]] and [[CES2]] are age-related but independent of growth hormone level. Sex seems to be an unlikely factor contributing to the regulation of [[CES1]] and [[CES2]].
|mesh-terms=* Adolescent
* Adult
* Aged
* Aging
* Animals
* Antineoplastic Agents, Phytogenic
* Blotting, Western
* Camptothecin
* Carboxylesterase
* Carboxylic Ester Hydrolases
* Child
* Child, Preschool
* Female
* Human Growth Hormone
* Humans
* Hydrolysis
* Infant
* Infant, Newborn
* Irinotecan
* Liver
* Male
* Methylphenidate
* Mice
* Middle Aged
* Sex Characteristics
* Subcellular Fractions
* Young Adult

|full-text-url=https://sci-hub.do/10.1124/dmd.109.028209
}}