RT Journal Article
SR Electronic
T1 Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.115.068957
DO 10.1124/dmd.115.068957
A1 Ronald N. Hines
A1 Pippa M. Simpson
A1 D. Gail McCarver
YR 2016
UL http://dmd.aspetjournals.org/content/early/2016/01/29/dmd.115.068957.abstract
AB 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, 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). Median cytosolic CES1 expression was 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). Median microsomal CES2 expression increased 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). 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 older individuals.