Citation:

Hines, R., P. Simpson, AND D. McCarver. Age-Dependent Human Hepatic Carboxylesterase 1 (Ces1) and Carboxylesterase 2 (Ces2) Postnatal Ontogeny. DRUG METABOLISM AND DISPOSITION: BIOLOGICAL FATE OF CHEMICALS. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 44(7):959-966, (2016).

Impact/Purpose:

The human hepatic carboxylesterases (EC 3.1.1.1) are a family of serine esterases that have an important role in the metabolism of numerous chemicals containing ester-, amide-, or thioester-bonds. Environmental chemicals for which the carboxylesterases are important for detoxication and disposition include the organophosphorous and pyrethroid insecticides. In the report, Pyrethroids: Evaluation of Data from DNTs and Consideration of Comparative Sensitivity, the United States Environmental Protection Agency opined that observed age-dependent sensitivity to pyrethroids is largely due to pharmacokinetic factors and in particular, the maturation of required metabolic processes (Document ID: EPA-HQ-OPP-2008-0031-0028 at http://www.regulations.gov). However, based on an evaluation of the major pharmacokinetic factors involved in pyrethroid metabolism in both the rat and human, as well as what is known regarding the developmental trajectories for these same factors, the study of differential sensitivity between juvenile and adult rats will unlikely inform potential human differential sensitivity. The objective of this study was to determine age-dependent changes in postnatal, human hepatic CES1 and CES2 specific content in both the microsomal and cytosolic compartments, evaluate interindividual variation in expression, and assess differences in expression as a function of sex and/or ethnicity/race. The study results demonstrate that infants < 3 weeks of age would exhibit significantly lower CES1- and CES2-dependent metabolic clearance compared to all older individuals. No differences were observed in the developmental trajectories of either enzyme as a function of sex. When assessed in a univariate analysis, differences were observed as a function of ethnicity/race, however, the significance of these factors failed to remain significance in a multivariate analysis that also included age.

Description:

Human hepatic carboxylesterase 1 and 2 (CES1 and CES2) are important for ester- and amide- bond containing pharmaceutical and environmental chemical disposition. Despite concern regarding juvenile sensitivity to such compounds, CES1 and CES2 ontogeny has not been well characterized. To define human hepatic microsomal and cytosolic CES1 and CES2 expression during early postnatal life, microsomal and cytosolic fractions were prepared using liver samples from subjects without liver disease [N=165, 1d-18 yrs]. Proteins were fractionated, detected and quantitated by western blotting. Median microsomal CES1 was lower among samples from subjects < 3 weeks of age (N=36) compared to the rest of the population (N=126; 6.27 vs 17.5 pmoles/mg microsomal protein, respectively; p<0.001; Kruskal Wallis test). Cytosolic CES1 increased sequentially with expression being lowest among samples from individuals between birth and 3 weeks of age (N=36), markedly greater among those from ages 3 weeks to 6 years (N=90), and then modestly greater still among those over 6 years of age (N=36; median values = 4.7, 15.8, and 16.6 pmoles/mg cytosolic protein, respectively; p values <0.001 and 0.05, respectively, Kruskal Wallis test). Microsomal CES2 also increased sequentially across the same three age groups with median values of 1.8, 2.9, and 4.2 pmoles/mg microsomal protein, respectively (p<0.001, both), whereas 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 < 3 weeks of age would exhibit significantly lower CES1- and CES2-dependent metabolic clearance compared to all older individuals.

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