Age-related inducibility of carboxylesterases by the antiepileptic agent phenobarbital and implications in drug metabolism and lipid accumulation

Abstract

Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids.

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

“…Differences in regulation of mouse hepatic CES isozymes between neonatal (10-day-old) and adult (70-day-old) mice have also been reported. Mouse Ces1d activity was preserved, Ces1e and Ces2c were upregulated, and Ces2e was downregulated by aging (Xiao et al, 2012). …”

Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

“…The change of carboxylesterases will lead to the alteration of the hepatic and intestinal hydrolytic biotransformation. Many studies show that diseases or pathologic states may modulate human and animal carboxylesterases (Xiao et al, 2012;Xiong et al, 2014). In this study, we report that the alteration of Ces1d and Ces1e, the two major hydrolytic enzymes, was involved in the metabolism of a wide range of drugs and other xenobiotics, in Figure 8.…”

“…Carboxylesterases constitute a class of hydrolytic enzymes that play important roles in drug metabolism (Quiroga & Lehner, 2011;Xiao et al, 2012). The change of carboxylesterases will lead to the alteration of the hepatic and intestinal hydrolytic biotransformation.…”

“…The liver expresses two major carboxylesterases, carboxylesterases 1 (CES1) and carboxylesterases 2 (CES2) (Xiong et al, 2014), whereas the gastrointestinal tract expresses predominantly CES2 (Satoh & Hosokawa, 2006). About 20% therapeutic agents undergo hydrolytic biotransformation (Xiao et al, 2012). In addition to the difference in tissue distribution, the two hydrolytic enzymes differ markedly in the hydrolysis of certain drugs.…”

“…Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as esters, amides, thioesters, and carbamates (Sanghani et al, 2009;Xiao et al, 2012). The liver expresses two major carboxylesterases, carboxylesterases 1 (CES1) and carboxylesterases 2 (CES2) (Xiong et al, 2014), whereas the gastrointestinal tract expresses predominantly CES2 (Satoh & Hosokawa, 2006).…”